European Journal of Medicinal Chemistry xxx (xxxx) xxx

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Review article

A review: Biologically active 3,4-heterocycle-fused coumarins

Fatemeh Salehian a, Hamid Nadri b, Leili Jalili-Baleh a, Leila Youseftabar-Miri c,
Syed Nasir Abbas Bukhari d, Alireza Foroumadi a, e, Tuba Tüylü Küçükkilinç f,
Mohammad Sharifzadeh g, Mehdi Khoobi a, e, *
a
Pharmaceutical Sciences Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 1417614411, Iran
b
Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
c
Department of Organic Chemistry, Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
d
Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Aljouf, Sakaka, 2014, Saudi Arabia
e
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
f
Hacettepe University, Faculty of Pharmacy, Department of Biochemistry, Ankara, Turkey
g
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Toxicology and Poisoning Research Centre, Tehran University of Medical Sciences,
Tehran, Iran

a r t i c l e i n f o a b s t r a c t

Article history: The combination of heterocycles offers a new opportunity to create novel multicyclic compounds having
Received 28 August 2020 improved biological activity. Coumarins are ubiquitous natural heterocycle widely adopted in the design
Received in revised form of various biologically active compounds. Fusing different heterocycles with coumarin ring is one of the
15 November 2020
interesting approaches to generating novel hybrid molecules having highlighted biological activities. In
Accepted 15 November 2020
Available online xxx
the efforts to develop heterocyclic-fused coumarins, a wide range of 3,4-heterocycle-fused coumarins
have been introduced bearing outstanding biological activity. The effect of heterocycles annulation at
3,4-positions of coumarin ring on the biological activity of the target structures were discussed. This
Keywords:
Coumarin
review focuses on the important progress of 3,4-heterocycle-fused coumarins providing better insight for
Antibacterial medicinal chemists on the design and preparation of biologically active heterocycle-fused coumarins
Antiviral with a significant therapeutic effect in the future.
Antioxidant © 2020 Elsevier Masson SAS. All rights reserved.
Antipsychotic
Anticholinesterase

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.1. Pyrrolocoumarin and indolocoumarin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.1.1. MDR reversal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.1.2. Antitumor activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.1.3. Anti-retroviral activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.1.4. DYRK1A inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.2. Furocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.2.1. Antifungal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.2.2. Antiprofilerative activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.2.3. Antioxidant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.2.4. Estrogen receptor modulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.3. Thienocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.3.1. Antibacterial and antifungal activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.3.2. RNA-binding activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1.3.3. Antiproliferative activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

* Corresponding author. The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 1417614411, Iran.
E-mail addresses: m-khoobi@tums.ac.ir, mehdi.khoobi@gmail.com (M. Khoobi).

https://doi.org/10.1016/j.ejmech.2020.113034
0223-5234/© 2020 Elsevier Masson SAS. All rights reserved.

Please cite this article as: F. Salehian, H. Nadri, L. Jalili-Baleh et al., A review: Biologically active 3,4-heterocycle-fused coumarins, European
Journal of Medicinal Chemistry, https://doi.org/10.1016/j.ejmech.2020.113034
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

1.4. Selenocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1.4.1. Anticancer and antioxidant properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Coumarin-fused five-membered rings with two heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Pyrazolocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1.1. Antibacterial and antifungal activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1.2. Anticancer property . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2. Imidazolocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2.1. Anticancer property . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Coumarin-fused saturated six-membered ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. Tetrahydropyridocoumarin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1.1. Antifungal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1.2. Antipsychotic activity (dopamine D4 receptor antagonists) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1.3. Bronchodilatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Protoberberine derivatives (polycyclic coumarin-based compounds) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Antibacterial and antifungal activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Coumarin-fused unsaturated six-membered heterocycle with one heteroatom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1. Pyridinocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1.1. Antibacterial and antifungal activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1.2. Anti-inflammatory and analgesic activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1.3. Antimalarial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1.4. Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.2. Pyridonocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.2.1. Anticancer property . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.2.2. Fibrotic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.3. Quinolinocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.3.1. Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.4. Iminopyridinocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.4.1. Antibacterial and antifungal activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.5. Benzofuro[3,2-b]pyridinocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.5.1. Anti-inflammatory and antimicrobial activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.6. Pyranocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.6.1. Antiproliferative property . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.6.2. Anticholinesterase activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.7. Benzopyranocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.7.1. Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.8. Dioxo-pyranocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.8.1. Antibacterial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.8.2. Antifungal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.9. Pyranoquinolino coumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.9.1. Anticholinesterase activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.10. Dihydropyrano pyrrolocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.10.1. Antimicrobial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.11. Pyranopyrimidinocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.11.1. Antimicrobial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.12. Spirooxindoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.12.1. Antibacterial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.12.2. Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Coumarin-fused unsaturated six-membered rings with two heteroatoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1. Pyrimidinocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1.1. Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1.2. Antithrombotic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1.3. Antibacterial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1.4. Antioxidant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.2. Imidazopyrimidinocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.2.1. Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.3. Pyrimidopyrimidinocoumarin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.3.1. Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7. Coumarin fused seven-membered ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.1. Thiazepinocoumarin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7.1.1. Anticancer and antioxidant activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Research ethics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Declaration of competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

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F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Abbreviations F oxysporum, Fusarium Oxysporum

G candidum, Geotrichum candidum
A mali, Alternaria mali GSK glycogen synthase kinase-3
A solani, Alternaria solani HIF1a Hypoxia inducible factor
A flavus, Aspergillus flavus M luteus, Micrococcus luteus
A niger, Aspergillus niger MIC minimum inhibitory concentration
A ochraceus Wilhelm, Aspergillus ochraceus Wilhelm MSCs Mesenchymal stem cells
B cereus, Bacillus cereus P chrysogenum Thom, Penicillium chrysogenum Thom
B subtilis, Bacillus subtilis P italicum, Penicillium italicum; PPA, Polyphosphoric
B cinerea, Botrytis cinerea acid
C albicans, Candida albicans P mirabilis, Proteus mirabilis
CDI 1,10 -Carbonyldiimidazole P aeruginosa, Pseudomonas aurignosa
CDK cyclin-dependent kinases Py Pyridine;
CHO Chinese hamster ovary Rh Solani, Rhizoctonia solani
C capsici, Colletotrichum capsici S enteritidis, Salmonella Enteritidis
DOX Doxorubicin SAR Structure-activity relationship;
DPPF 1,10 -Bis(diphenylphosphino)ferrocene S brevicaulis, Scopulariopsis brevicaulis
DYRK1A Dual-specificity tyrosine phosphorylation-regulated S marcescens, Serratia marcescens
kinase 1A SPHK1 sphingosine kinase 1
EAC Ehrlich ascites carcinoma S aureus, Staphylococcus aureus
ECA Ethyl cyanoacetate TFA Trifluoroacetic acid
E coli, Echerichia coli T. rubrum Trichophyton rubrum
E aerogenes, Enterobacter aerogenes

1. Introduction

The development or discovery of effective and inexpensive

drugs against disease is one of the main goals of researchers in the
field of medicinal chemistry. Over the years, great attention has
been paid to coumarin and its derivatives, which are versatile
molecules exhibiting a wide variety of biological properties
including antimicrobial, antiviral, anticancer, antioxidant, anti-
inflammatory, anti-tuberculosis, anti-influenza, anti-Alzheimer,
and anti-hyperlipidemia activities [1e15]. Coumarins (1) belong to
a-benzopyrone heterocyclic systems derived from Coumarouna
Fig. 2. Various types of heterocycle coupling with coumarin scaffold.

Fig. 3. The biological activities of 3,4-heterocycle fused coumarin derivatives (X is a

Fig. 1. Examples of clinically used coumarin derivatives.
hetero atom).
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F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Fig. 4. Representative of possible fusion of pyrrole/indole to the coumarin ring.

Scheme 2. Synthesis of pyrrolo[3,4-b]coumarins as antitumor agents.

Fig. 5. Structure and biological activities of pyrrolo[3,4-b]coumarin.

Fig. 7. Indolo[3,4-b]coumarins as anti-retroviral agent.

Scheme 1. Synthesis of Ningalin B derivative as MDR reversal agent.

Scheme 3. Synthesis of indolo[3,4-b]coumarins as DYRK1A inhibitor.

odorata Aube (Dipteryx odorata) first time [16]. They occur naturally
as a secondary metabolite in several plants, microorganisms, and
essential oils [17e19]. They have become a hot point in the me-
Fig. 6. Lamellarin I as MDR reversal agent.
dicinal chemistry because of their various pharmacological poten-
tials and less harmful effects against normal cells. The clinical
applications of certain members of this heterocycle have been

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F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Scheme 5. Synthesis of furocoumarins as anti-proliferative agents.

Fig. 8. Structure and biological activities of furo[3,2-c] coumarins.

Table 2
Anti-proliferative activity of furocoumarins 37a-37d.

Comp. No. X R IC50 (mM)

HCT-15 MCF-7

37a O CH3 212 112

37b O CH2CH3 10 16
37c N CH2CH2CH2CH2 8 19
37d N (CH3)2 252 50

Fig. 9. Chemical structure of Pterophyllin 2.

Fig. 10. Coumestrol as antiproliferative agent.

Scheme 4. Synthesis of furocoumarins.

reported extensively. For example, Phenprocoumon (2), Warfarin

(3), and Acenocoumarol (4) are considered as potent anticoagulant
agents (Fig. 1) [16,20]. Armillarisin A (5) is an antibiotic and
Hymecromone (6) is a choleretic and antispasmodic agent [21].
Ensaculin (7) is also a well-known coumarin-based structure hav-
ing valuable anti-dementia activity on the neurotransmitter system
with an acceptable pharmacodynamic profile [22]. It could be
concluded that the pharmacological properties and therapeutic
applications of coumarins strongly depend on the pattern of sub-
stitution [16].
The presence of two or more heterocyclic nuclei in one molecule
can enhance the biological effects of the target system or generate
new biological properties. When different heterocyclic rings are
linked to coumarin either as a substituent or as a fused component
into lactone (8,9) or benzene (10,11) ring, a synergistic effect of both
the rings is obtained in the target system (Fig. 2) [23]. The coupling
of the coumarin ring with different heterocycles has produced
novel hybrid molecules bearing highlighted biological activities.
Scheme 6. Synthesis of furocoumarin derivatives possessing anticancer activity.
Heterocyclic-fused coumarins are important and interesting
pharmacophoric moieties existing in many natural or synthetic
biologically active compounds [24]. They have provoked much in-
terest in researchers owing to diverse biological activities including
antimicrobial, antiviral, anticancer, anticholinesterase, antipsy-
chotic, anti-malarial, dopamine D4 receptor inhibition, adenosine
receptor binding ability, anti-fibrotic, anti-coagulant, estrogen re-
ceptor modulation, anti-inflammatory, analgesic, bronchodilation,
SPHK1 inhibition and DYRK1A inhibition (Fig. 3). Despite several
reviews on the biological aspects of coumarins, none of them has
focused specifically on 3,4-heterocycle fused coumarins and their
biological activities. In the present review, we try to find a corre-
lation between the type of heterocycle fused at 3 and 4 positions of

Table 1
Antifungal effect of compound 34.

Pathogen EC50 of compound 34

Botrytis cinerea R1 ¼ Isopropoxy, R2 ¼ Me > R1 ¼ Allyloxy, R2 ¼ H > R1 ¼ Allyloxy, R2 ¼ Me > Oshtol

Collecterichum capsica R1 ¼ Ethoxy, R2 ¼ Me > R1 ¼ Allyloxy, R2 ¼ H > Oshtol
Rhizoctorzia solani R1 ¼ OEt, R2 ¼ H > Oshtol > R1 ¼ OMe, R2 ¼ Me > R1 ¼ OEt, R2 ¼ Me > R1 ¼ Allyloxy, R2 ¼ H

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F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Table 3
Anticancer activity of furocoumarins 40a-40c.

Comp. No. R1 R2 R3 ED50 (mg/mL)

MCF-7 ZR-75-1 SK-BR-3

40a Me H Me 0.60 0.25 0.18

40b Et H Me 0.45 0.18 0.10
40c H H Me 4.00 4.00
40d H Cl Me 5.0 8.6 4.5 Fig. 12. Furocoumarin as Estrogen receptor modulator.
40e H OMe Me 5.0 >10 8.6
40f Me H H 5.5 >10 8.5
40g Et H H >10
40h H H H >10
40i H Cl H 7.0 >10 >10 1.1.1. MDR reversal activity
40j H OMe H 3.4 8.5 4.0 A major obstacle in the successful chemotherapy of cancers is
Tamoxifen 5.0 3.6 5.0 MDR. Extensive studies have been carried out during the past few
decades to improve the ability of chemotherapy by overcoming
MDR. The major mechanism of MDR in mammalian cells includes
the overexpression of human P-glycoprotein (P-gp, a plasma
membrane protein) by the MDR1 gene. Some alkaloids with the
core of pyrrolo[3,4-b]coumarin like lamellarins and ningalins acted
as nontoxic inhibitors of MDR pumps in different cancer cell lines
and could reverse MDR at noncytotoxic concentrations by inhibit-
ing P-gp-mediated drug efflux.
Boger et al. described a three-step synthesis protocol including
(1) N-alkylation, (2) lactonization and (3) decarboxylation started
from tetrasubstituted pyrrole (16) and phenethyl bromide (17),
resulted in permethyl ether of ningalin B (18) (Scheme 1) [26,27].
Fig. 11. Furocoumarin derivatives as antioxidant agents. Ningalin B (19) was synthesized by the demethylation of compound
18 with BBr3. Then, the cytotoxicity and MDR reverse activity of the
products (18 and 19) against L1210, HCT116, and HCT116/VM46 cell
coumarins and corresponding biological activities. This review is
lines were evaluated [28]. The results of the cytotoxic assay
classified according to the size (including five-, six- and seven-
exhibited that ningalin B (19) was 2.5- and 5-times more active
membered ring), type of heterocycles (including saturated and
than the O-methyl derivative (18) against HCT116 and L1210,
unsaturated), and the number (mono, di, and tri-) or nature of
heteroatoms on the ring (including nitrogen, oxygen, sulfur and
selenium heteroatoms) fused to 3 and 4 positions of coumarin. Each
section is fully discussed and compared in terms of the biological
activities of the compounds.
2. Coumarin-fused five-membered ring with one heteroatom
(Pyrrole, Indole, Furan, Thiophene, Selenophene).

1.1. Pyrrolocoumarin and indolocoumarin

A fusion of pyrrole or indole to the different sites of the

coumarin ring results in diverse molecular structures. There are
two possible sites for the fusion of coumarin with pyrrole or indole
ring producing pyrrolo[3,4-b]coumarin (12), pyrrolo[4,3-b] Fig. 13. Structure and bioactivities of thienocoumarins.
coumarin (13), indolo[3,4-b]coumarin (14), and indolo[4,3-b]
coumarin (15) derivatives (Fig. 4).

The pyrrolo[3,4-b]coumarin or chromeno[3,4-b]pyrrol-4(3H)-

one derivatives are one of the well-known natural marine alkaloids
and synthetic compounds having an appreciable biological signif-
icance (Fig. 5) [25e40]. Pyrrolocoumarins showed diverse biolog-
ical activities including multidrug resistance (MDR) reversal
[26e28], antitumor, and anti-retroviral activities. They were also
introduced as potent DYRK1A inhibitors [29e40]. The synthesis and
biological activities of this valuable coumarin-fused heterocycle are
discussed below. Scheme 7. Synthesis of thieno[3,2-c]coumarin derivatives as antimicrobial agents.

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F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Table 4
Antibacterial and antifungal activity of compounds 44e47.

Inhibition Zone (mm)

Comp. No. 1 2 3 4 5 6 7 8 9 10 11 12

44 9 0 0 10 8 8 13 0 0 0 8 0
45 10 0 0 10 11 0 14 0 10 16 13 13 Fig. 14. Thienocoumarin as RNA binding agent.
46 8 0 0 0 0 0 10 0 0 0 0 0
47a 0 0 0 0 0 0 13 10 12 0 10 11
47b 0 0 0 0 0 0 13 0 0 0 0 8
47c 0 0 0 9 0 0 0 0 0 0 0 0
47d 9 0 9 0 0 0 0 0 0 0 0 10
47e 10 0 9 9 0 0 13 0 0 0 0 0
Chloramphenicol 18 22 18 18 20 20 20 36 44 28 20 24

Organisms: 1) S. aureus, 2) B. cereus, 3) E. coli, 4) P. aeruginos, 5) S. marcescens, 6)

M. luteus, 7) C. albicancs, 8) T. rubrum, 9) A. flavus, 10) F. oxysporum, 11) S. brevicaulis,
and 12) G. candidum.

respectively. However, the MDR reversal activity of compound 18

was more effective than that of ningalin B and verapamil as the
standard inhibitors. On the other hand, compound 18 showed a
significant capability to reverse MDR by resensitizing a resistant
human colon cancer cell line (HCT116/VM46) to vinblastine (IC50
value: 0.002 mM) and doxorubicin (IC50 value: 0.01 mM) at 1 mM.
Lamellarin I (20), isolated from Didemnum sp., exhibited high Scheme 9. Synthesis of thienocoumarins as antiproliferative agents.

activity against MDR P388/Schabel cells at a non-toxic concentra-

tion (Fig. 6) [29]. The cytotoxicity of doxorubicin (DOX), vinblastine,
and daunorubicin against MDR cell lines was effectively increased
by compound 20. The MDR reversal activity of compound 20 was 9-
to 16- fold more than that of verapamil at 2 mM. It was also found
that compound 20 could modulate the resistance by inhibition of
the P-gp pump function.
1.1.2. Antitumor activity
A six-step reaction sequence was utilized for the preparation of
lamellarins (23) prepared from benzylisoquinoline derivative (21)
and compound 22 (Scheme 2) [30,31]. Anticancer activity of the
prepared lamellarins were evaluated against different cancerous
cell lines such as T47D and MDA-MB-231 (breast cancer cells), KB
(mouth carcinoma cells), HuCCA-1 (cholangiocarcinoma cells),
HepG2 and S102 (hepatocellular carcinoma cells), Hela (cervical
cancer cells), A549 (lung carcinoma cells), H69AR (multidrug
resistant lung cancer), HL-60 and P388 (leukemic cells), and MRC-5
fibroblast cells. The prepared lamellarins exhibited significant
cytotoxic activity. Especially the cytotoxic activity of lamellarins K
(23) against H69AR and HuCCA-1 cell lines (IC50: 4.3 and 3.4 mM,
respectively) was much more than that of the positive control,
etoposide (anticancer drug, IC50: 45.9 and 6.8 mM, respectively).
Lamellarin D (24) showed remarkable cytotoxic activity against all
the cell lines (IC50: 0.00008e3.2 mM). It was more toxic than the
standard drug, etoposide, against all the tested cell lines, except
MDA-MB-231 and S102 cell lines. No selective toxicity was
observed for most of the lamellarins. Interestingly, lamellarin N
(25) and dehydrolamellarin J (26) (Scheme 2) not only were
significantly more active than the other lamellarins and even than
etoposide as the positive control against most the cancer cell lines,
but also exhibited low toxicity against fibroblast cell line (MRC-5
IC50 > 97 mM).
Lamellarin D (compound 24) has been also reported as a potent
antiproliferative agent against various tumor cells, such as human
prostate cancer cells (DU-145, LNCaP) and human chronic mye-
logenous leukemia cells (K562) [32,33]. It has been also introduced
as a potent mitochondrial topoisomerase I inhibitor [34,35]. It has
been confirmed by various studies that the presence of full pen-
tacyclic pharmacophore, the planarity of the structure resulted
from saturation of the C5eC6 bond, and the presence of hydroxyl
groups at C7, C8 and C20 are crucial for remarkable cytotoxic and
topoisomerase I inhibition activity [31].
1.1.3. Anti-retroviral activity
HIV-1 integrase, a multi-domain enzyme, is required for the
integration of retroviral DNA into the host genome. It is an
endorsed target for developing anti-HIV agents. Sulfated marine
alkaloids have been introduced as an inhibitor of HIV-1 integrase
and HIV-1 replication [36]. Lamellarin a 20-sulfate (27) was

Scheme 8. Synthesis of thienocoumarins as antimicrobial agents. Fig. 15. Selenocoumarins and their bioactivities.

7
F. Salehian, H. Nadri, L. Jalili-Baleh et al.
Fig. 16. Selenocoumarin derivatives as anti-proliferative and antioxidant agents as well as MMP inhibitors.
isolated from unidentified ascidian and evaluated against pre-
integration complexes and HIV. Acceptable inhibitory activity was
obtained for the compound (Fig. 7) [36]. The screening of the in-
hibition of viral replication revealed that compound 25 could
inhibit HIV replication in early steps with IC50 value of 8.0 mM.
1.1.4. DYRK1A inhibitors
The dual-specificity tyrosine phosphorylation-regulated kinase
1A (DYRK1A) is one of the important target in neurodegenerative
diseases [37]. Researchers have designed various compounds as
DYRK1A inhibitors to treat neurological disorders. Several DYRK1A
inhibitors have been reported so far [37e39]. Neagoie et al. pre-
pared a series of lamellarin D analogs from the reaction of 2-
hydroxyphenylboronic acid derivatives (29) with indole de-
rivatives (28) through a Suzuki crosscoupling reaction, and a one-
pot deprotection/lactonization step (Scheme 3). The inhibitory ef-
fect of the indolocoumarins (30) was investigated against topo-
isomerase I and kinases (CDK5, GSK3, and DYRK1A). The study
showed that the presence of the hydroxyl group and its position at
the C-2/C-3 and C-10 could strongly affect the both activities.
Among all the prepared indolocoumarins, compound 30a bearing
hydroxyl group at C-3 and C-10 positions exhibited a strong topo-
isomerase I inhibitory activity (IC50: 38.5 nM) and weak kinase
activity (DYRK1A IC50: 0.3 mM). Although compound 30b bearing
hydroxyl group at C-2 showed no significant topoisomerase inhi-
bition activity, a selective and efficient DYRK1A inhibition effect
was observed with IC50 value of 67 nM. The molecular modeling
also revealed that the planar skeleton of compound 30b is the main
part creating a strong binding with the ATP active site of DYRK1A
similar to lamellarin D. In addition, the presence of bulky and
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European Journal of Medicinal Chemistry xxx (xxxx) xxx
lipophilic groups like eCH3, eCF3, eC6H4OH and 4-MeOC6H4 on
indoline moiety spontaneously decreased the kinase inhibition
activity of the target compounds.
1.2. Furocoumarin derivatives
Furocoumarins are found in a vast number of natural and syn-
thetic compounds with potential biological and pharmacological
activities [41]. Furocoumarins have gained interest due to the
antioxidant, cytotoxic, antifungal, NF-kB pathway inhibition and
estrogen receptor modulating activity. They have been candidate
for skin diseases treating, such as psoriasis [42]. Compounds having
furo[3,2-c]coumarin scaffold have shown interesting biological
activities encouraging researchers to find a new way for simple
preparation of this valuable framework (Fig. 8) [43e51].
1.2.1. Antifungal activity
Pterophyllin 2 (31) is a furo[3,2-c]coumarin derivative isolated
from methanolic extract of the Ekebergia pterophylla. It has
showed desirable inhibitory activity against phytopathogenic fungi
(Fig. 9) [43a].
Furo[3,2-c]chromen-4-ones (34) were synthesized via the re-
action of 4-hydroxycoumarins (32) with a-chloroketones (33) un-
der microwave irradiation (Scheme 4) [43band43c]. The products
showed antifungal activity against Botrytis cinerea, Collecterichum
capsica, Alternaria solani, Gibberella zeae, and Rhizoctorzia solani at
the concentration of 50 mg/mL (Table 1). The results revealed that
incorporation of the substituents like isopropoxy and allyloxy on
the coumarin nucleus affected the antifungal activity, so that these
compounds had 100% inhibition against Botrytis cinerea, and
F. Salehian, H. Nadri, L. Jalili-Baleh et al.
Fig. 17. Structure and biological activities of pyrazolocoumarins.
Scheme 10. Synthesis of aminopyrazolocoumarin
showed more activity than oshtole as a positive control (92.8%).
Isopropoxy-substituted derivative of compound 34 with R2 ¼ Me
showed the strongest activity against Botrytis cinerea (EC50: 1.72 mg/
mL), as compared to Osthole (EC50: 6.45 mg/mL). Allyloxy-
substituted compound with R2 ¼ H exhibited a better antifungal
activity against Botrytis cinerea and Collecterichum capsica rather
than osthole. In the case of Collecterichum capsica, OEt-substituted
compound with R2 ¼ Me revealed the higher antifungal activity
(EC50: 6.02 mg/mL) than allyloxy-substituted analogue with
R2 ¼ Me (EC50: 8.74 mg/mL) and Osthol (EC50: 16.83 mg/mL). Also,
the OEt-substituted compound with R2 ¼ H was the most effective
inhibitor of Rhizoctorzia solani (EC50: 3.57 mg/mL); whereas
allyloxy-substituted compound with R2 ¼ H had weaker antifungal
activity (EC50: 8.87 mg/mL) than osthole (EC50: 6.88 mg/mL).
1.2.2. Antiprofilerative activity
A series of furo[3,2-c]coumarin derivatives were prepared from
the reaction of compound 35 with alcohols or amines (36) in the
presence of Et3N as a catalyst and their potential anti-proliferative
activity was then screened against MCF-7 breast cancer cell line and
HCT-15 colon cancer cells (Scheme 5) [44]. The cytotoxicity results
showed that replacing of 2-methyl group (37a) with 2-ethoxy
group (37b) improved the activity by 22- and 7-times on HCT-15
and MCF-7, respectively (Table 2). Compound 37c bearing 2-
pyrrolidinyl group at furan ring exhibited 31.5- and 2.6-fold more
active than compound 37d bearing 2-dimethylamine substituent
on HCT-15 and MCF-7, respectively. Based on the results, com-
pounds 37b bearing ethoxy group (X ¼ O, R ¼ CH2CH3) and 37c
having pyrrolidinyl moiety (X ¼ N, R ¼ eCH2CH2CH2CH2-) were the
most active compounds against HCT-15 and MCF-7 cell lines. The
anti-proliferative activity of the tested compounds against both the
cell lines was found in order of 37b > 37a and 37c > 37d. Besides,
both compounds 37b and 37c diminished HCT-15 cancer cell pro-
liferation more than that of MCF-7. Compounds 37b and 37c had
appropriate DNA and BSA-binding affinity (K37b-
9
European Journal of Medicinal Chemistry xxx (xxxx) xxx
Scheme 11. Synthesis of pyrazolocoumarin derivatives as antibacterial and antifungal
agents.
Fig. 18. Pyrazolocoumarins as anticancer agents.
DNA ¼ 8.1  103 M1, K37c-DNA ¼ 1.1  104 M1, K37b-
BSA ¼ 5.1  104 M1, and K37c-BSA ¼ 7.6  104 M1). The acceptable
anticancer activity of compounds 37b and 37c was referred to the
desirable interaction and binding affinity of the compounds with
DNA.
Coumestrol (38) is a benzofuranocoumarin derivative (Fig. 10).
This naturally occurring antitumor compound is a protein kinase
CKII inhibitor against MCF-7 and HCT116 cells with 50% and 30%
growth inhibition at 50 mM, respectively [45b]. Cho and co-workers
studied the antitumor mechanism of compound 38 in hypoxic
prostate PC-3 cancer cells targeting hypoxia inducible factor 1a
(HIF1a) and sphingosine kinase 1 (SPHK1) signaling [46]. MTT assay
revealed that compound 38 could inhibit the activity of SPHK1, HIF-
1a, pAKT, and pGSK-3b expressions in a time- and dose-dependent
manner in hypoxic PC-3 cells. The results disclosed that compound
38 suppressed HIF-1 a accumulation via the SPHK1 suppression
pathway in hypoxic PC-3 cells.
Neo-tanshinlactone (40a) isolated from Salvia miltiorrhiza dis-
played potent and selective anti-breast cancer activity (Scheme 6)
[47a]. Compounds 40a showed 10-fold better activity and more
than 20-fold higher selectivity against ER þ cell lines (MCF-7 and
ZR-75-1) than tamoxifen. Wang et al. synthesized compounds 40a-
40j from substituted a-naphthols (39) and evaluated their anti-
cancer activity against several human tumor cell lines (MCF-7, ZR-
75-1, MDA MB-231, HS587-1, SK-BR-3, A431, SW620, and KB)
[47b]. The results of the best compounds are presented in Table 3.
The SAR studies revealed that the presence of the substitution at 4-
position of the ring A was important for the anticancer activity. The
order of the activity among compounds substituted at the 4-
position of the ring A (40a-40c) was ethyl (40b) ~ methyl
(40a) > no substituent (40c). The presence of the substituents like
Cl or OMe at position 6 of the ring B had no significant effect on the
activity. Also, the presence of methyl group on the furan moiety
(ring D) was critical for the anti-breast cancer activity of the target
compounds (40a-40e) resulting in better activity than unsub-
stituted analogs (40f-40j).
F. Salehian, H. Nadri, L. Jalili-Baleh et al.
Fig. 19. Structure and bioactivity of the imidazolocoumarin.
Scheme 12. Synthesis of imidazolocoumarin derivatives as anticancer agents.
1.2.3. Antioxidant activity
Wedelolactone (41), a phenolic derivative of Coumestan (42), is
a natural furocoumarin having potent antioxidant properties
(Fig. 11) [48]. Compound 41 could efficiently protect Mesenchymal
stem cells (MSCs) from hydroxyl radical-mediated oxidative dam-
age. Wedelolactone (41) could increase the viability of hydroxyl
radical-treated MSC cells. The antioxidant activity of this furo-
coumarin was 1.62 times higher than that of the standard antiox-
idant (Trolox). The antioxidant mechanism of wedelolactone (41)
has been ascribed as the direct radical scavenging via a single
electron transfer to radical adduct formation pathway. The results
showed that the catechol moiety of the compound was essential to
bind and scavenge DPPH radical for both of the pathways. Com-
pound 41 has been suggested as an effective therapeutic agent for
MSCs transplantation in bone-related diseases, especially osteo-
porosis, due to the phytoestrogenic and antioxidant effects.
Fig. 20. Structure and biological properties of tetrahydropyrido[3,4-c]coumarins.
10
European Journal of Medicinal Chemistry xxx (xxxx) xxx
Scheme 13. Tetrahydropyridocoumarin derivatives as antifungal agents.
1.2.4. Estrogen receptor modulators
Psoralidin (43), isolated from Psoralea corylifolia (an estrogenic
plant metabolite), is a benzofurocoumarin derivative having a wide
range of biological activities such as regulation of insulin signaling,
antibacterial, antioxidant, anti-inflammatory, anticancer, and anti-
depressant activities [49,50]. Liu et al. demonstrated that this
compound is a potent estrogen receptor (ER) signaling agonist
(Fig. 12) [51]. They described that compound 43 could activate the
classical pathway of ER-signaling in both ER-positive human breast
(MCF-7) and endometrial (Ishikawa) cell lines as well as non-
human cultured cells expressing shortly either ERa or ERb
(EC50 ¼ 3.68 and 6.88 mM, respectively). The relative binding af-
finity of psoralidin to both ERa and ERb was 0.56% and 0.042%,
respectively. IC50 values to replace the binding of E2 to both re-
ceptors were obtained 1.03 and 24.6 l mM, respectively.
1.3. Thienocoumarin derivatives
Thiophene structure is present in many natural products and
several pharmacologically active compounds. Thieno-fused
coumarin derivatives have gained much attention due to their
wide range of bioactivities such as antibacterial, antifungal, and
anticancer activities (Fig. 13) [52e55].
1.3.1. Antibacterial and antifungal activities
A series of thieno[3,2-c]coumarin derivatives (44e47) were
synthesized from 4-hydroxycoumarin (32) (Scheme 7) [52]. The
antibacterial activity of the products was evaluated against
different strains of bacteria (such as S. aureus, B. cereus, E. coli, P.
aeruginosa, S. marcescens, M. luteus) and fungus (C. albicancs, T.
rubrum, A. flavus, F. oxysporum, S. brevicaulis, G. candidum) (Table 4).
The aminothienocoumarin carboxylate (44) and carbohydrazide
(45) exhibited similar activity against P. aeruginosa (inhibition
zone ¼ 10 mm), less active than chloramphenicol as standard drug
(inhibition zone ¼ 18 mm). Replacement of the ester group (44)
with the carbohydrazide group led to the higher antifungal activity,
without any significant changes in the antibacterial activity. Ami-
noester derivative (44) exhibited remarkable activity against
S. aureus, P. aeruginosa, S. marcescens, M. luteus, C. albicans and
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Table 5
Antifungal activity of the pyridocoumarin derivatives.

Comp. No. The percentage of the growth reduction of bacteria and the mycelium of the fungus or mold in comparison with the control

Xanthomonas malvacearum Fusarium moniliform Rhizoctonia solani Powdery mildew Phytophthora infection Gray mold

80a 9 18 30 68 83 32
80b 9 6 2 0 0 21
80c 9 14 0 8 0 0
81a 0 20 13 38 83 0
81b 18 10 0 52 83 11
81c 0 22 15 0 0 0

Fig. 23. Structure and biological activities of protoberberine derivatives.

Fig. 21. Tetrahydropyridocoumarins as antipsychotic agents.

Table 6
Receptor binding data for the pyridocoumarins 83e86.

Ki (nM)a
1 2 3
Comp. No. R R R D4 D2 D3 D2/D4

83a OMe H H 1.5 436 60 291

83b Me H H 3.6 774 338 216
83c OMe 4-Cl H 8.7 >5800 2780 667
83d Me 4-Cl H 11 1170 e 106
83e OH 4-Cl H 2.4 2780 317 1160
83f OMe 4-F H 4.3 >5800 548 1350
83g Me 4-F H 7.5 >5800 2210 773
83h OMe 2-Cl H 34 >5800 2620 171
83i OMe 3-Cl H 17 5500 2630 324
83j OMe 3-Cl 4-Cl 61 >5800 e 95
83k OMe 4-Me H 2.6 1170 491 450
83l OMe 4-OMe H 84 >5800 e 69
83m OMe 4-CF3 H 8.2 3700 966 451
84 e e e >3300 e e e
85 e e e 7.9 >5800 591 734
86 e e e 74 >5800 e 78
a
Affinities for cloned human dopamine receptors.

Scheme 14. Synthesis of protoberberine derivatives of coumarin as antimicrobial

Fig. 22. Tetrahydropyridocoumarins as potential anticholinergic bronchodilators. agents.

11
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Scheme 16. Synthesis of pyridinocoumarin as antibacterial and antifungal agents.

additional nitrogen atom (47c-e) in the amine substitution of

Fig. 24. Structure and biological activities pyridinocoumarins.
Scheme 15. Synthesis of pyridinocoumarin derivatives as antimicrobial agents.
S. brevicaulis; while, addition of a chloroacetyl group reduced
antibacterial and antifungal activities of the compound (46) con-
firming the important role of the free amine group of thiophene
ring on the antimicrobial activity of the target compound. This may
be due to the effect of the amine groups producing positive charge
leading to the strongly attachment of the compound to the nega-
tively charged membrane of bacteria [53]. Compound 46 was just
active against S. aureus and C. albicans, less than the mother com-
pound (44). Nucleophilic substitution reaction of compound 46
with aromatic amines resulted in the formation of arylamino acetyl
derivatives (47a-e). Although, compounds 47d and 47e exhibited
moderate antibacterial activity against S. aureus, compounds 47a,
and 47b showed no antibacterial activity against all the tested
species of bacteria. Among arylaminoacetyl congeners possessing
thiophene ring, only compound 47d considerably expanded the
spectrum of the activity against more strains (such as P. aeruginosa,
S. marcescens, S. aureus), comparable to that of 47c and 47e. The
order of antibacterial activity against P. aeruginosa was
47d > 44 ¼ 45 > 47c > 46 ¼ 47a ¼ 47b ¼ 47e. The high antibacterial
activity of the compound 47d could be possibly due to the presence
of key sulfonamide pharmacophore.
Furthermore, among the prepared compounds, carbohydrazide
derivative (45) bearing hydrazone-substituted thiophene moiety
displayed considerable antifungal activity, whereas amino-
thienocoumarin carboxylate (44) with ester-substituted thiophene
and chloroacetyl amino derivative (46) with amide-substituted
thiophene, showed relatively low antifungal activity. The valuable
antifungal activity of compound 45 could be possibly attributed to
the pivotal role of hydrazide motif as versatile building block of
various antifungal agents [54]. Among compounds possessing
aminoacetyl derivatives (47a-47e) obtained from the nucleophilic
substitution of chloroacetyl amino compound (46), only compound
47a was the most active compound. The order of antifungal activity
was 45 > 47a > 44 > 46 > 47e¼ 47b¼ 47d > 47c.
In another study, benzothieno[2,3-c]chromen-6-one derivatives
(50a-e) were synthesized via condensation of substituted phenols
(49) with compound 48 and subsequently photocyclization reac-
tion (Scheme 8) [55]. The antibacterial activity assay of benzothieno
[2,3-c]chromen-6-one derivatives (50a-e) against S. aureus, E. coli,
B. subtilis, and S. typhosa showed the relationship between the
inhibitory effect and concentration of the compounds. The tested
compounds exhibited a much higher inhibitory effect on the
growth of bacteria at higher concentrations. The best inhibitory
effect on the growth of bacteria was obtained using 5 mg/mL of
compound 50a (R ¼ H and R1 ¼ NO2) against E. coli and S. typhosa
(inhibition zone: 15e18 mm). The methyl-substituted compound
(50b, R ¼ H and R1 ¼ Me) also showed more inhibitory activity at
5 mg/mL against B. subtilis compared with other bacterial species.
Presumably, the electronic effects of the substitution groups were
responsible for a better internalization of the compounds through

Table 7
Antibacterial and antifungal activities of compounds 93a-93g.

MIC (mg/mL)

Comp. No. R R1 R2 R3 1 2 3 4 5 6

93a H H H H 200 250 125 200 500 1000

93b H Me OMe H 100 62.5 250 200 500 1000
93c H Me H Benzo 62.5 200 250 250 500 1000
93d Me H H Benzo 100 125 62.5 100 >1000 1000
93e H Cl OMe H 200 62.5 200 250 500 >1000
93f H Cl H Benzo 62.5 200 62.5 100 1000 500
93g Me H OMe H 250 125 250 250 >1000 1000
Ampicillin 250 250 100 100 NT NT
Griseofulvin NT NT NT NT 100 500

Organisms: 1) S. aureus, 2) B. subtilis, 3) E. coli, 4) S. typhimurium, 5) A. niger, 6) C. albicans; NT: not tested.

12
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Table 8
Antibacterial and antifungal activities of compounds 96a-96l.

Comp. No. R1 R2 R3 R4 R5 Zone of inhibition (mm)

1 2 3 4 5 6 7 8

96a H H Cl H Cl 16 19 21 19 RD RD -ve -ve

96b OH H H Cl Cl 8 10 12 10 -ve -ve RD RD
96c OH Br H Cl Cl 21 20 19 22 -ve -ve -ve -ve
96d OH I H Cl Cl 16 8 18 14 RD RD þve þve
96e OH H OH H Cl 10 14 19 12 RD -ve RD RD
96f OH H Me Cl Cl 7 14 8 10 þve þve þve þve
96g OH Cl OH Cl Cl 18 22 22 20 -ve -ve RD -ve
96h OH I Me Cl Cl 15 12 9 12 þve þve þve þve
96i OH H H Cl OH 19 18 21 20 -ve -ve -ve -ve
96j OH Br H Cl OH 18 16 19 12 RD RD -ve RD
96k OH I H Cl OH 19 22 20 16 -ve -ve -ve -ve
96l OH I H Me OH 15 18 18 12 RD -ve -ve RD
Penicillin 24 24 22 22 NA NA NA NA
Nystatin NA NA NA NA -ve -ve -ve -ve

Organisms: 1) S. aureus, 2) B. subtilis, 3) E. coli, 4) S. typhimurium, 5) A. niger, 6) A. flavus, 7) F. moniliforme, 8) P. chrysogenum; þve, Growth; -ve: No growth; RD: reduced growth;
NA: not applicable.

Scheme 17. Synthesis of polyheterocyclic derivatives of pyridinocoumarin.

Scheme 19. Synthesis of pyridinocoumarin as an antimalarial agent.

Fig. 25. Polyheterocyclic derivatives of pyridinocoumarin as antibacterial agents.

Scheme 20. Synthesis of the pyridinocoumarins as anticancer agents.

Scheme 18. Synthesis of pyridinocoumarins as anti-inflammatory and analgesic
agents.

13
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Scheme 22. Synthesis of quinolinocoumarin derivatives.

1.3.2. RNA-binding activity

Fig. 26. Structure and pharmacological properties of pyridonocoumarins
Fukuzumi and co-workers performed a study on small mole-
cules binding to the precursor of miR-29a (pre-miR-29a) by the
fluorescent indicator displacement (FID) assay and subsequently
surface plasmon resonance (SPR) assay. The results suggested that
4H-thieno[3,2-c]chromen-4-one 51 (Fig. 14) could potentially be an
important structural motif to bind to pre-miR-29a and could be
considered as a suitable molecule for the detailed quantitative
structure-activity relationship (QSAR) studies [57].

1.3.3. Antiproliferative activity

Wittine et al. reported synthesis of thieno[3,2-c]coumarin de-
rivatives (53 and 54) from 4-hydroxycoumarin (32) (Scheme 9). The
prepared compounds were evaluated as an antiproliferative agent
against various human tumor cell lines including cervical carci-
Scheme 21. Synthesis of the pyridonocoumarin derivative.
noma (HeLa), colorectal adenocarcinoma-derived metastatic
(SW620), pancreatic carcinoma (MiaPaCa-2), breast epithelial
adenocarcinoma-derived metastatic (MCF-7) and hepatocellular
carcinoma (HepG2) as well as against normal diploid human fi-
broblasts (BJ) [58]. Antiproliferative activity of the coumarin[3,2-c]
thiophene hydroxamic acid derivatives (53a and 53b) against the
tested cell lines were more than coumarin[3,2-c]thiophene ureido
derivatives (54). The order of growth-inhibitory effects of the
hydroxamic acid derivatives against all the tested tumor cell lines
was 53b > 53c. In particular, the hydroxamic acid derivatives (53b
and 53c) exhibited high and selective antiproliferative effects on
HeLa cell lines with IC50 values of 8.84 and 9.47 mM, respectively.
Among coumarin[3,2-c]thiophene ureido derivatives, compound
54 showed remarkable selective cytotoxicity effect on Hela cell
lines (IC50: 9.43 mM).
Fig. 27. Pyridonocoumarin as fibrotic agent.

Fig. 28. Structure and biological activity of quinolinocoumarin.

the outer membrane of the Gram-negative or Gram-positive bac-

teria [56]. Scheme 23. Synthesis of quinolinocoumarin derivatives as anticancer agents.

14
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

1.4. Selenocoumarin derivatives

Selenium is essential for cell metabolism as a component of

glutathione peroxidase and other enzyme systems. The anticancer
effects of compounds bearing selenium were reported against
various cancer cell lines [59]. Two regioisomers of seleno-
coumarins, selenopheno[3,2-c] and [2,3-c]coumarins, exhibited
various pharmacological activities like antioxidant and anticancer
activities (Fig. 15) [60,63]. Fig. 29. Structure and biological activities of iminopyridinocoumarins

1.4.1. Anticancer and antioxidant properties

Two regioisomers of selenocoumarins (58e62) were prepared
from 3-bromocoumarin (55) or 4-(trifluoromethanesulfonyl)
coumarin (56) (Fig. 16) [60]. The compounds were then evaluated
for their cytotoxic activity against various tumor cell lines including
MES-SA (human uterus sarcoma), CCL-8 (mouse sarcoma), MCF-7
(human breast adenocarcinoma), MDA-MB-435s (human mela-
noma), HT-1080 (human fibrosarcoma), MG-22A (mouse hepa-
toma) and normal cell line of NIH3T3 (mouse fibroblasts). The
potency of the compounds for matrix metalloproteinases inhibition
was also investigated [60]. Most of the compounds showed no
significant toxicity against all the cell lines. However, compound 60
showed more cytotoxic activity against MES-SA cells (IC50: 9.4 mM)
than sodium selenite as reference compound (Na2SeO3 IC50:
29.0 mM). Selenophenocoumarins were much less toxic (LD50:
334e2000 mg/kg) than sodium selenite (LD50: 105 mg/kg). Among
the different derivatives, a few compounds were able to scavenge
free radicals. N-Methylpiperazyl aminomethyl derivatives (60 and
61) showed mild peroxyl radical scavenging activity (IC50: 62.0 and
87.0 mM, respectively). Compound 62 (R ¼ CH2N(CH2CH2)2O,
Ar ¼ 3-Pyridyl) was more active in peroxyl radical scavenging (IC50:
4.0 mM) than compounds 60 and 61. This could be due to the high
potential of pyridyl or aminopyridyl group to improve the antiox-
idant activity of the target compound [61,62]. Besides, by intro-
ducing the aminopyridyl group in the selenopheno[3,2-c]coumarin,
the inhibition of matrix metalloproteinase (MMP-2) was selectively
Scheme 25. Synthesis of iminopyridinocoumarin as an antibacterial and antifungal
agent.
increased. Selenolocoumarin functionalized with morpholine and
4-pyridyl amine group (63) having acceptable cytotoxic activity
against MCF-7 comparable with sodium selenite (IC50: 18.0 mM)
exhibited the highest selectivity for inhibition of MMP-2 (54%)
compared to N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhy-
droxamic acid as the standard inhibitor. Methylpiperazyl
substituted selenophenocoumarin (60) also inhibited angiogenesis
by 84% [60].
In another study, the antiproliferative effect of the regioisomeric
derivatives of selenocoumarins (60e62) was also screened against
HepG2, MCF-7, MH-22A (mouse hepatocarcinoma) tumor cell lines
(Fig. 16) [63]. The results showed that activity of the compounds
against tumor cell lines depended on their ability to induce
apoptosis. The compounds inhibited antioxidant enzyme system
activities (SOD, GPx and TrxR) and could diminish the ROS con-
centration (LD50: 572e2000 and 334e2000 mg/kg for selenopheno
[3,2-c] (60) and -[2,3-c]coumarins (61), respectively). The com-
pounds showed selectivity regarding redox enzyme activity con-
firming the important role of ROS in the mechanism of antitumor
action.

2. Coumarin-fused five-membered rings with two

Scheme 24. Synthesis of quinolino[3,2-c]coumarin derivatives as an anticancer agent. heteroatoms

2.1. Pyrazolocoumarin derivatives

Table 9
Cytotoxic activity of compounds 129a-129m assessed by the MTT reduction assay.
The wide spectrum of biological activities of pyrazole as one of
Comp. No. R IC50 (mM) the outstanding heterocyclic compounds including antimicrobial,
Hela MCF-7 K562 LS180 antifungal, antioxidant, antiviral, anti-tuberculosis, anti-
hyperglycemic, anti-inflammatory, and antitumoral activities has
129a 2-NO2 29.8 58.6 25.4 >100
129b 2-Cl >100 >100 >100 >100
129c 2-OMe >100 >100 >100 >100
129d 3-OMe >100 >100 >100 >100
129e 2-Me >100 >100 >100 >100
129f 4-NO2 88.2 >100 43.8 >100
129g 3-Br 83.6 31.4 38.8 >100
129h 4-Br 47.3 46.2 47.5 >100
129i 3-Cl >100 71.7 50.7 >100
129j 3-Me >100 52.2 57.4 >100
129k 4-Cl 37.7 41.8 37.5 >100
129l 4-OMe 98.5 62 >100 >100
129m 4-Me 43.6 66.7 56.2 >100
DOX e 0.256 0.137 0.157 0.180 Fig. 30. Structure and biological activities of the benzofuro[3,2-b]pyridinocoumarins.

15
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Fig. 32. Pyrano[3,2-c]benzopyran-5-ones as antiproliferative agents.

Scheme 26. Synthesis of benzofuro[3,2-b]pyridinocoumarins as anti-inflammatory
and antimicrobial agents.

encouraged many researchers to fuse this heterocycle to coumarin

derivatives [64e71]. Pyrazolocoumarin derivatives comprising of
coumarin and pyrazole moieties exhibited antibacterial, antifungal,
and anticancer activities (Fig. 17) [72,75].

2.1.1. Antibacterial and antifungal activities

Mulwad et al. synthesized a series of pyrazolocoumarin de-
rivatives (65a-65b) from 3-formyl-4-hydroxycoumarin (64) and
evaluated their antibacterial activities against S. aureus as a Gram-
positive and S. typhi as a Gram-negative bacterial strain (Scheme
10) [72]. The study showed that the phenyl substitution on pyr-
azole ring (65b) decreased the antibacterial activity against both
the bacteria (MIC value of 65a and 65b: 100 and 200 mg/mL,
respectively). Antimicrobial agents perform their activity via
various mechanisms including inhibition of the cell wall, protein or
nuclei acid synthesis, inhibition of the metabolic pathways in
bacteria synthesis or depolarization of the cell membrane [73].
Pyrazole skeleton is one of the well-known lead structures
inspiring medicinal chemists to design new generation of antimi-
crobial agents. It has been reported that attachment of the phenyl
or benzyl groups as lipophilic substituents to the nitrogen atom of
the pyrazole ring mostly resulted in the more antibacterial activity
than small substituents like hydrogen and methyl [74]; however,
Mulwad et al. were obtained different results reversely. The reason
for the different results in the studies may be attributed to the Scheme 27. Synthesis of pyranocoumarin derivatives as anticholinesterase agents.
different action mechanism of the compounds which could be
interesting for the researcher in the field of medicinal chemistry to
study on the rational antimicrobial mechanism of pyr- Table 10
azolocoumarins. It has been also reported that there is a threshold The anticholinesterase activities of compounds 141e142.

of lipophilicity for bacterial membrane permeabilization improving Comp. No. R IC50 (AChE, mM) IC50 (BuChE, mM) Selectivity
the antimicrobial activity, but further increase in the hydropho- 141a 2-F 2.9 36 12.4
bicity results in a loss of antimicrobial activity [75]. It seems more 141b 3-F 2.8 >50 >17.8
quantitative structure-activity relationship (QSAR) should be 141c 4-F 0.038 1.84 48.4
considered by medicinal chemist to better perceive the role of the 141d 2-Cl 1.5 4.8 3.2
141e 2-Me 3.7 17.8 4.8
substations in the activity of the compounds.
141f 3-Cl 0.48 21.8 5.2
El-Dean et al. synthesized a series of pyrazolo[4,3-c]coumarins 141g 3-Me 1.9 5.5 2.6
(68 and 69) from 4- hydroxycoumarin (32) in 3 steps (Scheme 11) 141h 3,4-Cl 0.044 1.27 28.9
[52]. The antibacterial and antifungal activities of the prepared 141i 2,4-Cl 0.831 0.566 0.68
142a 2-F 1.8 41 22.8
compounds were investigated against different strains of bacteria
142b 3-F 2.0 >50 >25
(S. aureus, B. cereus, E. coli, P. aeruginosa, S. marcescens and M. luteus) 142c 4-F 2.17 2.17 1
and fungi (C. albicans, T. rubrum, A. flavus, F. oxysporum, S. 142d 2-Cl 1 11.2 11.2
142e 3-Cl 7.4 38.4 5.2
142f 3-Me 0.79 14.3 18.1
Donepezil 0.014 5.38 384.3

Selectivity of AChE: IC50 (BuChE)/IC50 (AChE).

brevicaulis, and G. candidum). The synthesized compounds (68 and

69) exhibited lower antimicrobial activity than chloramphenicol
and clotrimazole, as standard drugs for antibacterial and antifungal
assay, respectively. Compound 68 showed higher antifungal activ-
ity than compound 69. Although, compound 68 showed no
Fig. 31. Different pharmacological activities of pyranocoumarin derivatives.

16
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

antibacterial activity against all the bacterial species, compound 69

exhibited antibacterial activities against S. aureus, E. coli, and
P. aeruginosa. The results confirmed that the dominant mechanism
responsible for antibacterial and antifungal activities in this study
might be different for the compounds. The increase in the per-
centage of the nitrogen elements could be a reasonable explanation
of the improved antifungal activity of compound 68 rather than
compound 69. Improved electron density and more cationic Scheme 28. Synthesis of benzopyranocoumarin derivatives as anticancer agents.
structure could result in strong interactions with cell membrane
which could be one of the possible reasons for better antifungal
activity of compound 68 than compound 69.

2.1.2. Anticancer property

A series of substituted pyrazolocoumarins (73e75) were syn-
thesized via a two-step reaction including (1) the reaction of 4-
chloro-3-formylcoumarin (70) with phenylhydrazine hydrochlo-
ride (71) and (2) ring cyclization by pyridine with the aid of
piperidine as catalyst (Fig. 18) [76]. The anticancer activity of the
coumarinepyrazole hybrids (73) was investigated in human pros-
tate (DU-145), lung adenocarcinoma (A549), and cervical cancer
cell lines (HeLa) using MTT assay. Doxorubicin (DOX) and nocoda-
zole were applied as standard drugs. Most of the compounds were
inactive against the cancerous cell lines. The results revealed that
compound 73a bearing para methoxy phenyl group was the most
active compound against A549 (IC50: 27.0 mM) without any signif-
icant cytotoxic activity against other cancerous cell lines (DU-145
IC50: 175.0 and HeLa IC50: 190.0 mM). Compound 73b having methyl
group at meta position of the phenyl ring showed moderate cyto-
toxic activity against A549 (IC50: 43.0 mM). None of the prepared
compounds showed appropriate cytotoxic effect against DU-145
(IC50  100), except compound 73c and 73d having mild toxicity
(IC50: 53.0 and 60.0 mM, respectively).
2.2. Imidazolocoumarin derivatives
Imidazole plays an essential role in the development of new
drugs in medicinal chemistry, especially for cancer treatment [77].
Owing to the valuable biological profiles of the coumarin and
imidazole scaffolds, hybridization of these interesting structures
has encouraged researchers to prepare the compounds having
improved synergistic effects (Fig. 19) [78e80]. There is only one
report related to the anticancer activity of the imidazolocoumarins
and therefore various derivatives of this scaffold could be consid-
ered as potential candidate for other biological activities.
Fig. 34. Structure and biological activity of dioxo-pyranocoumarin.
2.2.1. Anticancer property
Han et al. synthesized a series of chromeno[3,4-d]imidazole-
4(1H)-one derivatives (75) from compound 74 and evaluated their
anticancer activities on U87-MG, HCT116, and PC-3 cell lines
(Scheme 12) [80]. This study showed that among all the derivatives
having simple phenyl substituent attached to the N1, the cytotoxic
activity of the pyridine-4-yl (75a) or quinolin-3-yl (75b) derivatives
was more than other substituted compounds such as pyridine-3-yl,
3-NH2-C6H4, 2-Me-C6H4, 4-OH-C6H4, and 3-NHSO2-(4-FeC6H4)e
C6H4. When the substituent was changed from simple phenyl group
to 4-CH2CN substituted phenyl group, the anticancer activity of the
target compound was slightly improved. Among this group, pyri-
dine-3-yl (75c) or quinolin-3-yl (75d) derivatives exhibited
appreciable cytotoxic activity against HCT116 cells (IC50: 29.37 and
28.4 mM, respectively), confirming the key role of the nitrogen atom
on the heterocyclic substituent as hydrogen acceptor site in
appropriate binding with the corresponding target. The SAR study
also demonstrated the important role of cyano group on the phenyl
ring attached to the N-1, possibly as a hydrogen acceptor center
improving the interaction of the compound with the corresponding
target. Among all the substituents attached to the N-1, 4-
CH2CNeC6H4 (75c and 75d) and 4-C(CH3)2CNeC6H4 (75e and
75f) showed the best performance in cytotoxic activity. Compound
75e bearing pyridine-3-yl substituent at C-6 position showed lower
anticancer activity against PC-3 cells (IC50: 38.20 mM) than com-
pound 75f with quinoline-3-yl substituent at the C-6 position (IC50:
19.76 mM). In addition, when compound 76 converted to compound
77, anticancer activity improved against HCT116 (IC50 value
changed from 20.40 to 1.40 mM). Compound 77 showed excellent
anticancer activity against a broad spectrum of the cell lines (IC50:
1.40, 3.55, 1.70, 3.50, and 9.50 mM against HCT116, SW620, MCF-7,
CT26, and A549, respectively). This research also revealed that
compound 77 bearing 4-C(CH3)2CNeC6H4 at N-1 position, methyl

Fig. 33. Structure and biological activity of benzopyranocoumarin. scheme 29. Synthesis of dioxopyranocoumarins as antibacterial agents.

17
F. Salehian, H. Nadri, L. Jalili-Baleh et al.
Scheme 30. Synthesis of dioxopyranocoumarin derivatives used as antibacterial
agents.
group at N-3 position, tert-butoxy and methyl groups at C-2 of the
imidazole moiety, and quinoline-3-yl at the C-6 position of
coumarin was the best anticancer agent. The flow cytometry
experiment demonstrated that compound 77 could arrest the cell
cycle of SW620 at G0/G1 and induce apoptosis in a concentration-
dependent manner. Further in vivo anticancer experiments on
subcutaneous HCT116 tumor model in nude mice showed that
compound 77 could inhibit tumor growth by 52.96% at 80 mg/kg/
48 h after 20 days.
3. Coumarin-fused saturated six-membered ring
3.1. Tetrahydropyridocoumarin
Tetrahydropyridine scaffold is found in numerous natural and
synthetic compounds exhibiting interest pharmacological proper-
ties such as neuroprotective effect [81]. Tetrahydropyrido[2,3-c]
coumarin derivatives are considered as potential antifungal, anti-
psychotic, and bronchodilator agents (Fig. 20) [82e84].
3.1.1. Antifungal activity
Mandal et al. synthesized a series of substituted tetrahydro[3,4-
c] and benzo[h]tetrahydro pyrido[3,4-c] coumarins via
Scheme 31. Synthesis of dioxopyranocoumarin derivative.
18
European Journal of Medicinal Chemistry xxx (xxxx) xxx
Scheme 32. Synthesis of pyrano[3,2-c]chromene-2,5-dione as antifungal agent.
condensation of b-ketoester 78 with aenaphthol (39) or m-cersol
(79), respectively, and evaluated the fungicidal activities against
Xanthomonas malvacearum, Fusarium manilliform, Rhizoctonia sol-
anis, Powdery mildew, Phytophthora and Gray mold (Scheme 13,
Table 5) [82]. Tetrahydrobenzopyridocoumarin derivatives (80)
showed higher activity than the series of tetrahydropyr-
idocoumarins (81). Compounds 80a and 81a having unprotected
amine group (R ¼ H) showed the highest activity among all the
compounds against most of the fungi. N-Acetylation of compound
80a led to a significant decrease in the fungicidal activity (80b). N-
Acetylation of compound 81a also resulted in a significant decrease
in the antifungal activity of compound 81b against Fusarium man-
illiform and Rhizoctonia solanis. Furthermore, N-methylation led to
the lower activity of compounds 80c and 81c against Powdery
mildew and Phytophthora infection than their analogs (80a and 81a).
The results clearly confirmed the crucial role of the free amine on
antifungal activity of the target compounds. It has been suggested
that the free NH is essential for the high potency of the compounds,
while the protection of NH by groups changing the electronic
contribution of the nitrogen and tetrahydropyridin part decreases
the antifungal activity. The presence of methyl substituent at po-
sition 8 of the coumarin moiety (81a) showed lower potential to
improve antifungal activity than the 7,8-benzocoumarin analogs
(80a) indicating the key role of the lipophilic phenyl group resulting
Fig. 35. Structure and biological activity of pyranoquinolinocoumarins.
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

in the more penetration via permeation mechanism and subse-

quently more activity (see Table 6).

2.1.2. Antipsychotic activity (dopamine D4 receptor antagonists)

Pyridine-fused coumarin derivatives have been synthesized
from different phenols and beketoesters and introduced as selec-
tive human dopamine D4 receptor antagonists (Fig. 21) [83]. The
affinity of the synthesized tetrahydrochromeno[3,4-c]pyridin-5-
ones (82) towards the dopamine D2, D3, and D4 receptors have
been determined in vitro by assessing their ability to displace the
dopamine ligand [3H]-spiperone from cloned human dopamine
receptor subtypes expressed in Chinese hamster ovary (CHO) K-
1 cells. The type of the substituents at different positions of the
phenyl or benzyl parts and the length of the side chain affected
significantly receptor binding activity of the target compounds. The
binding activity decreased by the elimination of the methylene side
chain (83a compared with 84) or replacement of the phenyl group
with pyridine (83a compared with 86). Compound 85 possessing Fig. 36. Structure and biological activity of dihydropyranopyrrolocoumarin
additional carbon in the chain length showed improved selectivity derivatives.
for D4 versus D2 receptor in comparison to compound 83a. The
ability of the best active compounds to block stimulation of mito-
genesisintrinsic activity in transfected CHO 10001 cells with DA D4
receptors was also investigated to study the intrinsic activity of the
compounds in comparison with quinpirole as a full agonist of
dopamine. The compounds having 20% or less intrinsic activity
(83b, 83g, 83k, and 83m) were antagonists, while compounds
showing more than 20% intrinsic activity (83a, 83c, 83e, 83f, 83i,
and 85) were partial agonists.

3.1.3. Bronchodilatory activity

A series of 3-substituted benzopyrano[3,4-c]pyridin-5-ones Scheme 34. Synthesis of dihydropyranopyrrolocoumarin derivatives as antimicrobial
were synthesized and introduced as a potential anticholinergic agents.

bronchodilator confirmed by several in vivo studies (pig and dog

models) (Fig. 22) [79]. Among various derivatives of 87 bearing
various amine groups attached to the carbon a (*), the most potent
bronchodilators were compounds containing the 3-azabicyclo
[3.2.2]non-3-yl and methoxy groups (87a and 87b ID50: 35.0 and
113.0 mg/kg for dog model, respectively). The results showed that
the steric hindrance in the carbon a position is critical for the su-
perior bronchodilator activity. Addition of a methyl group on the
carbon a improved often the potency and pulmonary selectivity of
the compound. Compound 88a without substituent on coumarin
ring and having noncyclic amine group showed the highest pul-
monary selectivity (21.6).
4. Protoberberine derivatives (polycyclic coumarin-based
compounds)
Protoberberines, a member of alkaloids, have attracted consid-
erable attention over the decades because of the important bio-
logical activities and their presence in many traditional medicines
as active components [85e89]. Coumarin analogs of proto-
berberine exhibited antibacterial and antifungal activities (Fig. 23)
[90].

4.1. Antibacterial and antifungal activities

Jadhav et al. prepared a series of protoberberines (90a-f) from

coumarin-4-acetic acid 89 via five-step reaction including (1)
esterification, (2) amidation with 2-phenethylamines, (3) Bischler-
Napieralski, (4) reduction and (5) Mannich reactions (Scheme 14)
[90]. The results of the gel electrophoresis technique for DNA
cleavage assay showed that all the tested compounds (90a-f) were
inactive against E. coli, but compounds 90e and 90f bearing 7,8-
benzo substituent on the coumarin moiety were capable to cleav-
age DNA of S. aureus and A. niger. It may be due to the presence of
the angularly fused cyclic skeleton preventing the growth of the
pathogenic organism. This study confirmed the critical role of the
additional benzene ring fused to the coumarin skeleton in cleavage
of the genomic DNA of the bacteria as well as its effect on the lip-
ophilicity of the system leading to more penetration of the target
compounds via permeation mechanism and subsequently more
antibacterial activity.
Scheme 33. Synthesis of pyranoquinolinocoumarin derivatives.

19
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Fig. 37. Structure and biological activity of pyranopyrimidino coumarin derivatives.

5. Coumarin-fused unsaturated six-membered heterocycle

with one heteroatom
Scheme 36. Synthesis of pyranopyrimidinocoumarin derivatives as antimicrobial
agents.
5.1. Pyridinocoumarin derivatives

Pyridine and its derivatives are important chemical compounds Table 11

Antibacterial activity of some pyranopyrimidinocoumarin derivatives.
because of their diverse range of biological applications in different
fields [91]. Pyridinocoumarin core produced by the fusion of Comp. Inhibition zone (mm)
coumarin and pyridine parts exhibited a wide range of biological 1 2 3 4 5 6 7 8 9 10 11 12 13
activities [92] such as antimicrobial [93e95], anti-inflammatory a
160a 28 11 19 10 20 10 e e 12 11 20 e e
and analgesic [96], antimalarial [97], anticancer (Fig. 24) [98]. 160bb 18 e 19 e e e 18 20 e e e 16 18
166aa 22 18 16 10 13 12 e e 21 12 20 e e
167aa 29 22 18 18 21 20 e e 14 16 18 e e
5.1.1. Antibacterial and antifungal activities 167bb 21 e 22 e e e 20 19 e e e 14 12
A series of pyridine-fused coumarin derivatives 93a-g were 169bb 18 e 17 e e e 19 19 e e e 19 15
synthesized via Mannich-type reaction between pyridinium salts 170ab 20 e 22 e e e 21 20 e e e 18 19
170bb 20 e 22 e e e 20 19 e e e 19 17
(91) and 4-hydroxycoumarin derivative (92) or 4-chloro-3- 170cb 23 e 22 e e e 23 22 e e e 19 19
formylcoumarin (70) and evaluated for their antibacterial and 170db 23 e 22 e e e 25 23 e e e 19 20
antifungal activities against Gram-positive bacteria (B. subtilis and 171b 20 e 22 e e e 21 22 e e e 20 19
S. aureus), Gram-negative bacteria (E. coli and S. typhimurium) and Amoxicillin 29 12 20 11 36 10 e e e e e e e
Ampicillin 26 e 25 e e e 26 27 e e e e e
fungi (A. niger and C. albicans) (Scheme 15) [93]. The results showed
Mycostatin e e e e e e e e 12 20 26 22 24
that the antimicrobial potency of the compounds strongly depen-
ded on the pattern of the substituents (Table 7). All the compounds Organisms: 1) S. aureus, 2) B. subtilis, 3) B. cereus, 4) P. aeruginosa, 5) E.coli, 6)
E. aerogenes, 7) S. marcescens, 8) P. merabitis, 9) A. niger, 10) P. italicum, 11)
exhibited significant activity against Gram-positive bacteria (MIC F. Oxysporum, 12) A. ochraceus Wilhelm, 13) P. chrysogenum Thom.
250 mM) compared with ampicillin as the reference drug (MIC: a
Amoxicillin was used as the reference compound.
250 mM). Introduction of methoxy as electron releasing group and b
Ampicillin was used as the reference drug.
methyl as lipophilic part (93b or 93g) improved the activity of the
compounds against Gram-positive bacteria compared with simple
derivative (93a). Also, benzo and chloro groups as lipophilic could (95), compounds 96c, 96i and 96k showed equipotent antifungal
significantly improve the antimicrobial activity of the target com- activity as compared to nystatin against all fungi including A. niger,
pounds (93d-93f). The compound bearing both chloro substituent A. flavus, F. moniliforme, P. chrysogenum with MIC value of 100 mg/mL
on the phenyl ring and additional benzene ring in coumarin scaf- (Scheme 16, Table 8) [94]. Compounds 96c and 96g exhibited good
fold (93f) exhibited the highest activity towards both E. coli and inhibitory effect as potent as penicillin against S. typhi and E. coli,
S. aureus (MIC: 62.5 mg/mL), as compared to the standard drug, respectively. Compounds 96g and 96k exhibited better antibacte-
ampicillin. Furthermore, compounds 93g showed better activity rial profile against B. subtilis than the other compounds and pro-
(MIC: 200 mg/mL) than griseofulvin as reference drug (MIC: 500 mg/ duced an inhibition zone similar to that of Penicillin. Compound
mL) against fungal pathogen C. albicans. 96g having 1,3-di-hydroxyl and 2,4,5-tri-chloro groups in the
In another study, among different derivatives of pyridocoumarin
having pyrazole moiety (96a-96l) synthesized by the reaction of 4-
hydroxycoumarin derivative (94) with a,beunsaturated ketones

Scheme 35. Synthesis of pyranopyrimidino coumarin derivatives. Fig. 38. Structure and biological activities of spirooxindolocoumarin derivatives.

20
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

compound. The order of the analgesic activity was similar to the

order of the anti-inflammatory potency. Also, compound 103d
displayed lower toxicity than diclofenac potassium as the standard
drug (LD50: 2368 and 1988 mg/kg, respectively).

5.1.3. Antimalarial activity

Scheme 37. Synthesis of spirooxindolocoumarin derivatives as antibacterial and
anticancer agents.
Gorlitzer et al. synthesized pyridine-fused derivative of
coumarin (106) from compound 104 and N,N-diethyl-1,4-
pentadiamine (105) and evaluated its antimalarial activity. Com-
pound 106 showed the antimalarial activity against the
chloroquine-resistant plasmodium falciparum strain Dd2 with IC50
value of 1100 nM (IC50 for chloroquine as reference drug: 140 nM)
(Scheme 19) [97].

5.1.4. Anticancer activity

phenyl ring displayed higher antibacterial activity than the other
compounds.
In another study, polyheterocyclic derivatives of pyr-
idinocoumarin were synthesized through the reaction of 3-
aminopyrazol-5-ones (97) with salicylaldehydes (98) and acetyl-
acetic ester (99). The prepared compounds (100) showed antibac-
terial activity against different Gram-positive strains (S. epidermidis
and S. aureus) (Scheme 17) [95]. Compound 100a exhibited the
most activity against S. epidermidis and methicillin-resistant
S. aureus (MIC: 6.3 and 25.0 mM, respectively) and compound
100b displayed significant antibacterial property against
S. epidermidis (MIC: 25.0 mM) (Fig. 25).
Various pyridinocoumarin derivatives were synthesized from
the reaction of 4-aminocoumarin (107) with various a,b-unsatu-
rated carbonyl compounds (108e111). Anticancer activity of the
prepared compounds (112e115) was evaluated against Ehrlich As-
cites Carcinoma (EAC) cells (Scheme 20). The results showed
acceptable antitumor activity of the pyridinocoumarin derivatives
(112e115) against EAC cells (IC50: 0.12e0.13 mM) which was more
than 5-fluorouracil as the standard drug (IC50: 0.38 mM) [98]. The
high cytotoxic activity of the compounds could be ascribed to the
great effect of the pyridine, quinolone, or indandione ring through
various mechanisms like growth inhibition, apoptosis, or

5.1.2. Anti-inflammatory and analgesic activities

Hosni et al. synthesized benzopyranopyridine derivatives (103)
via Michael reaction of compound 101 with malononitrile (102)
followed by hydrolysis. The anti-inflammatory and analgesic ac-
tivities of the products were tested (Scheme 18) [96]. It was
revealed that both pyridine nucleus and five-membered ring
bearing one heteroatom in furanyl benzopyranopyridine de-
rivatives were essential for anti-inflammatory and analgesic activ-
ities. Among the tested compounds, compound 103d showed high
protection against induced edema, more than 89%, with high per-
centage of the plasma prostaglandin (PGE2) inhibition, comparable
with diclofenac as the reference drug (more than 62%). The degree
of anti-inflammatory potency was 103d > 103a > 103b > 103c. The
analgesic activity of the compounds on adult male albino rats
confirmed the high potency of compound 103d which was nearly 2
times more than diclofenac as the standard anti-analgesic

Fig. 39. Structure and biological activities of pyrimidinocoumarin derivatives. Scheme 38. Pyrimidinocoumarins as anticancer agents.

21
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

5.2. Pyridonocoumarin derivatives

Pirfenidone (PFD, 116), 5-methyl-1-phenylpyridine-2(1H)-one,

Scheme 39. Synthesis of pyrimidine-fused coumarin derivatives as anticancer agents.
angiogenesis inhibition on the anticancer activity of the target
compounds as reported previously [99e101]. All the compounds
had similar cytotoxic activity and the electronic properties of the
substituents on the pyridine moiety had no effect on the activity of
the products.
is used for the treatment of Idiopathic Pulmonary Fibrosis (IPF)
(Fig. 26). The 2-pyridone scaffold is ubiquitous in many natural and
synthetic compounds displaying oncogenic properties. 5-Pyridyl-2-
oxopyridine derivatives such as milrinone (117) and amrinone (118)
have also shown great potential for the treatment of congestive
heart failure [102e104]. The valuable features of pyridine-2(1H)-
one framework together with the interesting biological activity of
the coumarin derivatives encouraged many medicinal chemists to
design and prepare new multicyclic compounds bearing both
scaffolds. Pyridonocoumarin derivatives have been screened for
their biological activities and some of them exhibited anticancer
and fibrotic potency [105,106].
5.2.1. Anticancer property
El-Said et al. reported a series of pyridinocoumarin as PFD an-
alogs anticancer derivatives against EAC cell lines (Scheme 21)
[105]. They found that cyclization of compound 119 at positions 3
and 4 of the coumarin ring with malononitrile (102) resulted in a
reduction of pyridinocoumarin 120 activity (IC50: 245.7 mM).
Compound 120 had no cytotoxic effect against EAC cell lines
compared to positive control doxorubicin (IC50: 68.13 mg/mL).

5.2.2. Fibrotic activity

Despite the reported anti-fibrotic activity of PFD alone, the
annulation of PFD to coumarin ring (121) led to an increased fibrotic
potential on lung fibrosis in the rat model (Hydroxyproline
content ¼ 193.07 mmol/Lung) and toxicity on liver and kidney
functions (Fig. 27) [106]. Also, compound 121 showed a reduction
in LDH (lactate dehydrogenase) activity, protein concentration, and
total cell count (macrophages, neutrophils, and eosinophils)
compared with PFD alone.

5.3. Quinolinocoumarin derivatives

The diverse pharmacological properties of quinoline and its

derivatives have attracted more attention to employ this scaffold in
the design of new multicyclic heterocycles. quinoline derivatives
fused with various heterocycles have displayed wide pharmaco-
Scheme 40. Synthesis of pyrimidinocoumarin derivatives as antithrombotic agents. logical activity such as anticancer, antimycobacterial, antimicrobial,

Table 12
In vitro antiplatelet potency of compounds 183, 185e157 against arachidonic acid (AA), U46619, and ADP induced aggregation in rabbit PRP and inhibitory potency against
thrombin induced clot retraction in rat PRP.

Comp. No. R R0 Inhibition of platelet aggregation IC50 (mM) Inhibition of clot retraction IC50 (mM)

ADP 3 mM AA 50 mM U46619 1 mM Thrombin 20 U/mL

183a e OMe e e e e
183b e SMe e e e e
183c e Pyrrolidino e e e e
183d e Morpjolino e e e
185a NH2 H e e e e
185b NH2 NH2 e e e e
185c NH2 OMe e e e e
185d NH2 SMe e e e e
185e NH2 Pyrrolidino e e e e
185f NH2 Morpjolino e e e e
186a SMe Pyrrolidino e e e e
186b SMe Piperidino e e e e
186c SMe Morpjolino e e e
187a Pyrrolidino SO2Me 13 15 4 13
187b Piperidino SO2Me 18 16 21 27
187c Morpjolino SO2Me 16 21 3 37
Aspirin - e >500 61 e e

22
F. Salehian, H. Nadri, L. Jalili-Baleh et al.
Fig. 40. Structure and biological activity of imidazopyrimidinocoumarin derivatives.
anticonvulsant, anti-inflammatory, and cardiovascular activities
[107]. There is just one report related to the biological activity of
benzopyranoquinolinone scaffold, a class of heterocycles produced
from combination of coumarin and quinoline moieties (Fig. 28)
[108e110].
5.3.1. Anticancer activity
A series of 6H-1-benzopyrano[4,3-b]quinolin-6-ones (123) were
synthesized via the reaction of 4-chloro-3-formylcoumarin (70)
with different anilines (122) (Scheme 22) [108]. The anti-
proliferative property of the products was evaluated in vitro
against four human cancer cell lines including myeloid (K562),
breast (MDA-MB 231), colon (Colo-205), and neuroblast (IMR32).
Compounds 123a, 123b, 123c, 123g, 123h, 123i and 123j exhibited
good activity against MDA-MB 231 (IC50 ~ 8.0e16.0 mM), and
compounds 123a, 123c, 123g and 123j were active against Colo-205
(IC50~ 11.0e18.0 mM). Among all the tested compounds, compound
123c was the most active compound against Colo-205 and MDA-
MB 231 cell lines with IC50 values of 11.0 and 8.0 mM, respec-
tively. All the tested compounds showed moderate activity against
IMR32 (43.0 > IC50 > 20.0 mM), and were more active than hermine
as reference compound (IC50 > 45.0 mM). Compound 123e showed
significant activity against IMR32 (IC50: 23.0 mM). It has been sug-
gested that sirtuin inhibition activity could be the possible mech-
anism of anticancer activity of the compounds against Sirt1.
Compound 123d showed 48% inhibition of Sirt1, much less than
suramin as standard drug having 79% inhibition at 10 mM.
A family of 7,12-dihydro-6H-chromeno[4,3-b]quinoline de-
rivatives (126) was prepared using 4-hydroxycoumarin (32), aro-
matic amines (124), and aldehydes (125) (Scheme 23) [109]. The
antitumor activity of the products was investigated against A-549
and MCF-7 cell lines using convenient MTT assay. Some of the
compounds were stronger than cisplatin as the reference drug
against both the cell lines. Among tested compounds, compound
126a (R1 ¼ 4-Me and R2 ¼ Ph) was the most active compound
against MCF-7 cells with IC50 value of 0.52 mM, and compound 126b
Fig. 41. Structure and biological activity of pyramidopyrimidinocoumarin
23
European Journal of Medicinal Chemistry xxx (xxxx) xxx
Fig. 42. Structure and biological activities of thiazepinocoumarin.
(R1 ¼ 4-Me and R2 ¼ 3-OMe-C6H4) showed the most activity against
A-549 cell lines (IC50: 0.05 mM). However, compound 126c was
inactive against both the cell lines (IC50 > 100.0 mM). Compound
126a was also oxidized by 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) resulting in the formation of a pyridine ring
(127). However, the aromatization process led to a significant
decrease in the cytotoxic activity (IC50 > 100.0 mM). The order of
anticancer activity against MCF-7 was 126a > 126b > 126c > 126d
and also against A-549 was 126b > 126a > 126c > 126d.
In another study, 7H-chromeno[4,3-b]quinoline-6,8-dione de-
rivatives (129a-129m) were synthesized from 1,3-cyclohexadione
(128), benzaldehydes (125), and 4-hydroxycoumarin (32), and
their cytotoxic activity were evaluated against four different human
cancer cell lines; HeLa (human cervical adenocarcinoma), K562
(human chronic myelogenous leukemia), LS180 (human colon
adenocarcinoma), and MCF-7 (human breast adenocarcinoma)
(Scheme 24) [110]. The tested compounds showed weak activity
against LS180 cells (IC50 > 100.0 mM) and mild activity against Hela,
K562, and MCF-7 cell lines (IC50: 25.0e100.0 mM) compared to the
DOX as the reference drug (IC50 < 0.26 mM) (Table 9). The results
demonstrated that the substituent group on the phenyl ring
affected the cytotoxic activity significantly. For example, compound
129a with a nitro group at the ortho position of the phenyl ring
showed the highest activity against K562 and Hela cell lines (IC50:
25.0 and 29.0 mM, respectively), while compounds 129b-129e were
the weakest derivatives against all four human cell lines
(IC50 > 100.0 mM). Also, calcium channel antagonist activity of the
tested compounds was evaluated and only 3-Cl substituted com-
pound (129i) exhibited 3 folds stronger activity (IC50: 599 nM) than
the other derivatives which was nearly 7 folds weaker than nifed-
ipine (as the reference drug, IC50: 91.4 nM).
5.4. Iminopyridinocoumarin derivatives
Iminopyridine complexes such as osmium (II) arene iminopyr-
idine complexes have gained much interest as strong anticancer
agents having IC50 values in nanomolar range [111]. Iminopyr-
idinocoumarin is a class of the fused coumarin scaffolds, which
exhibited valuable pharmacological properties such as antibacterial
and antifungal activities (Fig. 29). The synthesis and biological ac-
tivities of this valuable compound are discussed below [112].
5.4.1. Antibacterial and antifungal activities
Iminopyridinocoumarin derivative (132) was prepared from
dimethylaminoethylene derivative 130 and 2-aminopyridine (131).
Compound 132 showed strong antibacterial and antifungal activ-
ities against B. subtilis, S. aureus, E. coli, and A. niger compared with
streptomycin and mycostatine (MIC: 50 mg/mL) as the references
(Scheme 25) [112]. Although no study was performed or suggested
for the appropriate antimicrobial effect of the target compound
F. Salehian, H. Nadri, L. Jalili-Baleh et al.
Scheme 41. Synthesis of pyrimidinocoumarin derivatives as antibacterial agents.
(132), it seems that the presence of nitrogen-rich heterocycle and
free amine controlling the charge and subsequently affinity of the
compound to the cell membrane and also ion chelation ability of
the compound play key roles in the antimicrobial activity.
5.5. Benzofuro[3,2-b]pyridinocoumarin derivatives
Benzofuran scaffolds have drawn much attention due to their
wide range of biological activities and potential applications as
pharmacological molecules. Diverse biological activities of benzo-
furan derivatives have been reported in the literature including
antimicrobial [113], analgesic, anti-inflammatory [114], antipara-
sitic [115], antihyperglycemic [116], antitumor, and kinase inhibi-
tion activities [117].
Also, pyridine derivatives possess exciting antibacterial, anti-
viral, antioxidant, anti-diabetic, anti-cancer, anti-malarial, anal-
gesic potency, anti-amoebic, enzyme inhibition, anti-inflammatory
activities [118]. Studies on the biological activities of the benzo-
furano[3,2-b]pyridines have shown interesting biological activities
[119e121] inspiring researchers to fuse this valuable heterocycle to
other biologically active frameworks. The fusion of benzofur-
anopyridine unit with coumarin gave rise to a pentacyclic system
Scheme 42. Synthesis of pyrimidin-annulated coumarin derivatives.
24
European Journal of Medicinal Chemistry xxx (xxxx) xxx
exhibiting valuable antimicrobial and anti-inflammation properties
(Fig. 30) [122].
5.5.1. Anti-inflammatory and antimicrobial activities
Khan et al. synthesized polycyclic heterocycles 135 having
benzofuranopyridine and coumarin rings from various 4-
bromomethylcoumarins 133, salicylonitrile 134, and orthoesters
via a three-step reaction including (1) allylic substitution, (2)
intramolecular condensation and (3) ring closure reaction. The
authors evaluated anti-inflammatory and analgesic activities of the
products (Scheme 26) [122]. LD50 values of the prepared com-
pounds were more than 800 mg/kg body weight. Among the tested
group, compound 135a showed significant anti-inflammatory ef-
fects at 200 and 300 mg/kg dose level (81% and 89% inhibition,
respectively). The evaluation of the analgesic activity of the com-
pounds by acetic acid-induced abdominal constriction revealed
that compound 135b was the most potent compound with 78%
inhibition of inflammation at 300 mg/kg dose level (maximum
possible effect ¼ 24.4%). Also, all the tested compounds exhibited
antimicrobial activity against Pseudomonas cichorii (MIC: 25 mg/
mL), and no activity was observed against Micrococcus aureus. All
the compounds could also inhibit the growth of Aspergillus fumi-
gatus at 25 mg/mL and Penicillium wortmannin at a concentration of
100 mg/mL.
5.6. Pyranocoumarin derivatives
Pyran derivatives are the nucleus of many compounds with
wide biological and pharmacological properties such as anticancer,
anti-microbial, antifungal, anti-osteosarcoma, and antihistaminic
activities [123]. Also, pyrano-fused heterocycles are an important
class of structural motif in many natural products and synthetic
drugs with antifungal, insecticidal, anticancer, anti-HIV, anti-in-
flammatory, and antibacterial activities [124,125]. Different
F. Salehian, H. Nadri, L. Jalili-Baleh et al.
Scheme 43. Synthesis of imidazopyridinocoumarin as an anticancer agent.
Scheme 44. Synthesis of pyrimidopyrimidinocoumarin as an anticancer agent.
Scheme 45. Synthesis of thiazepine-annulated coumarins.
pharmacological activities have been described for the compounds
bearing the pyrano[3,2-c]chromene-5(4H)-one nucleus (Fig. 31)
[124,125].
5.6.1. Antiproliferative property
A series of halogenated 2,4-diaryl-4H,5H-pyrano[3,2-c]benzo-
pyran-5-ones (136) were prepared and their anticancer activity was
evaluated against MCF-7 cell lines. All compounds showed a
remarkable antiproliferative effect against MCF-7 (Fig. 32) [124]. All
of the compounds were more potent than the reference drug ful-
vestrant (ICI 182780, Estrogen receptor antagonist). Nevertheless,
all the compounds had no appropriate estrogenicity or affinity to-
wards recombinant human estrogen receptors alpha protein.
5.6.2. Anticholinesterase activity
Pyranocoumarin derivatives have been introduced as a suitable
pharmacophore for the preparation of novel cholinesterase in-
hibitors (ChEIs). Two series of pyrano[3,2-c]chromene derivatives
bearing N-benzyl pyridinium part (140) were synthesized in the
presence of magnetic nanocatalyst via a three-step procedure
including (1) reaction between pyridine-3 or 4-carbaldehydes (137)
and malononitrile (103), (2) reaction with 4-hydroxycoumarin (32)
and (3) the reaction of compound 138 with benzyl chlorides (139)
(Scheme 27). Then, the products (140) were evaluated against
acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)
(Table 10) [125]. Both derivatives showed significant inhibitory
activity against AChE with IC50 values less than 7.4 mM. The study
revealed that anti-ChE activity and AChE/BuChE selectivity index
strongly depends on the type and position of substituent on the
benzyl pendent. In term of the AChE inhibitory activity, 3-
pyridinium analogs were more active than 4-pyridinium analogs
except 3-Cl and 4-F substituted derivatives. Despite the similar
range of BuChE inhibitory activity of both 4-F analogs (141c and
142c), compound 141c showed the highest anti-AChE activity at a
25
European Journal of Medicinal Chemistry xxx (xxxx) xxx
nanomolar concentration (IC50: 0.038 mM) and higher BuChE/AChE
selectivity (Sl ¼ 48.4). The docking study demonstrated that pyr-
anocoumarin part of the compound 141c interacts with the cata-
lytic active site (CAS) of the AChE and N-benzyl pyridinium part
interacts with the peripheral anionic site (PAS) of the enzyme.
5.7. Benzopyranocoumarin derivatives
Benzopyran ring is an important group of organic compounds
displaying pharmacological properties such as antimicrobials,
antitumor, anti-inflammatory, anticancer, anti-HIV, and anticoag-
ulants activities [126]. There is only one report related to the bio-
logical activity of this group of compounds (Fig. 33) [127].
5.7.1. Anticancer activity
Benzopyrano[3,2-c]chromene-6,8-diones (143) were synthe-
sized through three-component reaction between 4-
hydroxycoumarin (32) to 1,3-cyclohexadione (128) and benzalde-
hydes (125) (Scheme 28) [127]. In vitro cytotoxic studies of the
compounds were performed against four different human cancer
cell lines (Raji, HeLa, LS180, and MCF-7). According to the results, all
the compounds showed weak-to-moderate anti-tumor activities
with IC50 values ranging from 49.0 to more than 100 mM. No
meaningful relationship was observed between the effect of the
substituents and the cytotoxic effect of the compounds. Among the
prepared compounds, derivatives containing methyl group in po-
sition 2, 3, or 4 of the phenyl ring showed the weakest activities
(IC50 > 100 mM) against all the cell lines except for Raji cells with
IC50 value of 73e80 mM. The results also revealed that the presence
of methoxy group, especially at the meta position of the phenyl ring
in compound 143 (R ¼ 3-OMe), resulted in partially more cytotoxic
activity against all the cell lines (IC50: 49e99 mM). Owing to the
high potential of furocoumarin scaffolds to bind to the DNA re-
ported previously, it could be assumed for the target compounds
(143) to have the possible ability for interaction with nucleobases in
DNA causing the cytotoxic effect and possibly the presence of
electron donor group improved the interaction [128].
5.8. Dioxo-pyranocoumarin derivatives
The pyranone (pyron) scaffold as one of the most abundant
heterocycles in naturally occurring organic compounds exhibited
various biological activities such as antitumor, anti-inflammatory,
antibacterial, antityrosinase, and anti-HIV activities [129]. The
fusion of 2H-pyran-2-one ring to the coumarin ring produced a
series of pyrano[3,2-c]chromene-2,5-dione (dioxo-pyr-
anocoumarin) reported as antibacterial and antifungal agents
(Fig. 34) [130e132].
5.8.1. Antibacterial activity
Tetrazoles have exhibited a wide range of biological and phar-
macological properties such as antibacterial, antifungal, anticancer,
antiviral, antimalarial, and anti-tubercular activities. This valuable
heterocycle are considered as one of the key pharmacophore
encouraging medicinal chemist to employ it in the drug design and
discovery [133]. A series of pyrano[3,2-c]chromene-2,5-dione de-
rivatives having tetrazole moiety (146) were synthesized via a
three-step reaction including (1) Knoevenagel condensation be-
tween compound 144 and ethyl cyanoacetate (ECA), (2) cyclization
by polyphosphoric acid (PPA), and (3) 1,3-dipolar reaction between
compound 145 and NaN3 (Scheme 29) [130]. Antibacterial activity
of the products (146) was screened against S. aureus, S. typhi and
E. coli. The MIC values of the compounds against S. aureus, S. typhi
and E. coli (100e150 mg/mL) were far inferior to that of cloxacillin
(MIC: 10.0 mg/mL), ciprofloxacin (MIC: 5.0 mg/mL) or gentamycin
F. Salehian, H. Nadri, L. Jalili-Baleh et al.
(MIC: 5.0 mg/mL) as the standard drugs.
Pyranobenzopyran derivatives (151e153) were also prepared
through a three-step synthetic method including (1) Knovenagel
condensation of compound 63a with diethyl malonate (147), (2)
Michael addition of compound 148 and ethyl aceto acetate (EAA,
149) or acetyl acetone (150), and (3) pechmann condensation of 151
with EAA (Scheme 30) [131]. Antibacterial activity of the pyr-
anobenzopyran derivatives (151e153) against S. aureus, E. coli and
S. typhi was compared with dioxo-pyranocoumarin 148 and the
standard drugs. All the prepared compounds showed no appro-
priate antimicrobial activity (MIC > 110.0 mM) compared with the
standard drugs (ciprofloxacin MIC: 5.0; cloxacillin MIC:10.0 and
gentamycin MIC: 5 mM). Compound 151 showed better antibacterial
activity against S. aureus which could be due to intrinsic antimi-
crobial property of catechol moiety in the structure of the com-
pound than that of the mother analogue [134].Compound 153 also
showed better antibacterial activity against both S. aureus, S. typhi
strains than compound 148 which could be due to the presence of
the fused pyranonebenzopyranone system [135]. Compound 152
showed higher activity against E. coli than other strains. Compound
153 having more lipophilic methyl substituted group showed
acceptable activity against both Gram positive and Gram negative
strains (S. aureus, S. typhi and E. coli).
In another study, compound 155 was prepared by the reaction of
3-formyl-4-hydroxy coumarin 62a and hippuric acid 154. Com-
pound 155 exhibited appropriate antibacterial activity towards
S. typhi (MIC: 50 mg/mL) (Scheme 31) [78]. Comparison between
antibacterial activity of compound 148 and compound 155 showed
that addition of the amide bond could improve the antimicrobial
activity of the target compounds.
5.8.2. Antifungal activity
Zhang and his coworkers described synthesis and antifungal
activity of pyrano[3,2-c]chromene-2,5-dione derivatives (158 and
159) against five phytopathogenic fungi (B. cinerea, C. capsici,
A. solani, A. mali, and Rh. solani) [132]. Various derivatives of pyrano
[3,2-c]chromene-2,5-dione were synthesized by the reaction of 4-
hydroxycoumarin derivatives (32) with beketoesters (156 or 157)
(Scheme 32). All derivatives of compound 158 exhibited more
antifungal activity against B. cinerea (inhibition rate: 35e67%) than
azoxystrobin as reference drug (inhibition rate: 34%), except com-
pound 158a (R1 ¼ O(CH2)3CH3, R2 ¼ H, R3 ¼ Me) and 158b
(R1 ¼ OMe, R2 ¼ H, R3 ¼ Me). Compound 158c (R1 ¼ H, R2 ¼ Et,
R3 ¼ Me) showed superior antifungal activity against B. cinerea,
C. capsici, A. solani, more active than the standard drug. Among
compounds 158, only one derivative substituted by R1 ¼ H, R2 ¼ Et,
and R3 ¼ Me showed better antifungal activity against B. cinerea
and C. capsica (EC50 values of 0.141 and 0.115 mM, respectively)
compared to azoxystrobin (the control, EC50: 0.158 and 0.222 mM,
respectively). The results revealed that the presence of lipophilic
ethyl group at 4-position of the compound (R2 ¼ Et) has more effect
than other substituents on the antifungal activity. Compound 158b
was more active than compound 158d confirming the crucial effect
of CF3 group (R2 ¼ CF3) to improve the antifungal activity of the
target compounds. The results of the study confirmed that the level
of the hydrophobicity generated by substituents at 3,4-positions
had great effect on the activity of the dioxo-pyranocoumarins.
5.9. Pyranoquinolino coumarin derivatives
The pyranoquinolines are one of the attractive scaffolds having
various biological effects such as anticancer [136], psychotropic,
anti-inflammatory, and antibacterial activities [137]. The great po-
tential of 5,6,7,8-tetrahydroquinolin-4-amine (THQA) as an
important part of Tacrin analogs and coumarin moiety as a well-
26
European Journal of Medicinal Chemistry xxx (xxxx) xxx
known pharmacophore inhibiting AChE aroused the interest of
the researchers to synthesize new pyranoquinoline-fused
coumarin derivatives having high anticholinesterase activity
(Fig. 35) [138].
5.9.1. Anticholinesterase activity
A series of tetrahydrochromeno[30 ,4’:5,6]pyrano[2,3-b]quino-
lin-6(7H)-one derivatives (162) were prepared via a two-step re-
action including a three-component reaction between
benzaldehydes (125), malononitrile (102), and 4-hydroxycoumarin
(32) to yield compound 160 which was then reacted with cyclo-
hexanone (161) via €nder
friedla reaction. The pyr-
anoquinolinocoumarins 162 were screened against AChE and BChE
and their activity was compared with tacrine as reference drug
with IC50 value of 410 and 32.0 nM against AChE and BuChE,
respectively (Scheme 33) [138]. Among them, 4-fluorophenyl
substituted derivative (162a) was the most active compound
against AChE (IC50: 5.00 nM), while benzodioxole-5-yl substituted
(162b) showed high activity against BuChE (IC50: 570.0 nM). By
replacing the aromatic substitutions (R ¼ phenyl, 4-pyridyl, 2-
thienyl) with a methyl group, more inhibitory potency against
BChE and less inhibitory activity against AChE were obtained.
Docking studies on the active compound showed both occupation
of PAS and CAS of AChE and mixed-type kinetic mode of the
enzyme inhibition. It was revealed that p-p stacking between
phenyl moiety of compound 162a (R ¼ 4-fluorophenyl group) and
the phenyl side chain of Tyr334 as well as hydrogen bonding be-
tween the carbonyl group of the coumarin ring and the hydroxyl
group of Tyr121 were the main factor stabilizing the complex of
ligand-protein in the active site.
4.10. Dihydropyrano pyrrolocoumarin derivatives
The 4H-pyran derivatives have attracted immense interest in
medicinal chemistry due to their various pharmacological and
biological activities, such as antimicrobial, mutagenicity, anti-
proliferative, antitumor activities [139]. Heterocycles having fused
dihydropyranopyrrole nucleus have attracted much attention due
to the synergistically improved effect of the heterocycles. There is
only one report on dihydropyrano[2,3-b]pyrrole derivatives fused
to the coumarin ring as antimicrobial agents (Fig. 36) [140].
5.10.1. Antimicrobial activity
Al-Haiza et al. synthesized compound 165 via the reaction of
compound 163 and 4-bromophenacyl bromide (164) (Scheme 34)
[140]. The antibacterial and antifungal activities of the compounds
were evaluated against Gram-positive bacterium (S. aureus,
B. subtilis and B. cereus), Gram-negative bacterium (E. coli, P. aeru-
ginosa, and E. aerogenes), and fungi (A. niger, P. italicum, and
F. oxysporum). The study revealed that the ring-closing and for-
mation of dihydropyranopyrrolo moiety decreased the antibacte-
rial and antifungal activities of the target structure (165) compared
with that of the mother compound (163). The order of the anti-
microbial activity was 163 > 165. Compound 165 showed signifi-
cant antibacterial activity against B. subtilis, more than amoxicillin
as the standard drug. However, compound 165 exhibited lower
antifungal activity against all the fungi compared to mycostatine as
a standard drug. Only one pyranopyrrolocoumarin was prepared in
this study limiting appropriate interpretation regarding parameters
affecting the antimicrobial activity of the compound. However, it
seems that the presence of the free amine is crucial to reach great
antibacterial activity.
F. Salehian, H. Nadri, L. Jalili-Baleh et al.
5.11. Pyranopyrimidinocoumarin derivatives
Pyrano[2,3-d]pyrimidine derivatives possess various pharma-
cological activities including antifungal, antitumor, hep-
atoprotective, and antihypertensive activities [141]. In the light of
the valuable antimicrobial activity of this heterocycle, pyranopyr-
imidinocoumarin derivatives were prepared via fusing pyranopyr-
imidine moiety with the coumarin at 3 and 4 positions of the ring.
The new heterocyclic systems possessed notable biological activ-
ities such as antibacterial and antifungal properties (Fig. 37)
[140,142,143].
5.11.1. Antimicrobial activity
Al-Haiza et al. and El-Agrody et al. used pyrano derivatives of
coumarin (160) as an intermediate for the preparation of pyr-
anopyrimidino coumarin derivatives (168 and 167) and evaluated
their activity against Gram-positive bacteria (S. aureus, B. subtilis, B.
cereus) and Gram-negative bacteria (E. coli, P. aeruginosa,
E. aerogenes) (Scheme 35, Table 11) [131,140,142]. The biological
screening indicated that cyclization of compound 160 had no sig-
nificant impact on antibacterial activity of compound 166 and 167.
However, among the prepared compounds having a 4-
bromophenyl group (160a, 166a and 167a), compound 167a
showed the best antibacterial activity towards S. aureus, B. subtilis,
P. aurignosa, and E. aerogenes compared to the standard drug
amoxicillin [140]. In addition, the antibacterial evaluation of the
pyranopyrimidinocoumarin derivatives with R ¼ CH3 showed
moderate antibacterial activity of the compounds (166b and 167b)
against all the tested bacteria (S. aureus, B. cereus, S. marcescens, P.
merabitis) compared to ampicillin as the reference drug [143].
The authors also examined the antifungal activity of the pyr-
anopyrimidinocoumarin derivatives (166 and 167) against A. niger,
P. italicum, and F. oxysporum. Compound 167a showed the most
activity against A. niger compared to the standard fungicide
mycostatine [140]. The antifungal activity of compounds 160b,
166b, and 167b was also investigated against A. ochraceus Wilhelm
and P. chrysogenum Thom which was lower than mycostatine as the
standard drug [143].
A series of pyranotriazolopyrimidine derivatives (169a-d) were
synthesized by hydrazinolysis of compound 168. Corresponding
triazolopyrimidine (170) were then synthesized via cyclization of
compound 169 by appropriate carboxylic acid chlorides/diethyl
oxalate. The pyrimidotriazine scaffold (171) was similarly prepared
by reaction of compound 168 and triethylorthoformate (Scheme
36) [142,143]. The biological screening of the synthesized com-
pounds (169, 170 and 171) against various bacteria (S. aureus,
B. cereus, S. marcescens, and P. merabitis) and fungal strains
(A. ochraceus Wilhelm, P. chrysogenum Thom) revealed that all the
compounds had similar antibacterial activity compared to ampi-
cillin as the reference drug (Table 11). Compounds 168 and 169
showed nearly the same antifungal activity against A. ochraceus
Wilhelm and P. chrysogenum Thom. Compounds 170a-d and 171
were the most active compounds against A. ochraceus Wilhelm and
P. chrysogenum Thom, while compounds 160b, 167b, 168, and 169b
exhibited moderate activity against A. ochraceus Wilhelm and
P. chrysogenum Thom.
5.12. Spirooxindoles
Spirooxindole framework is considered as an important struc-
tural motif and is available in several medicinal agents and natural
products [144]. Spirooxindole derivatives exhibited a wide spec-
trum of biological activity including antimicrobial, anti-
inflammatory, antitumor, antimalarials, anti-HIV and antiviral,
anticancer activities [145,146]. Taking account of the application of
27
European Journal of Medicinal Chemistry xxx (xxxx) xxx
pyranocoumarin and spirooxindole scaffolds in medicinal chemis-
try, a series of pyranocoumarin derivatives bearing spirooxindole
moiety have been synthesized and introduced as promising can-
didates for drug discovery such as antibacterial and anticancer
compounds (Fig. 38) [147,148].
5.12.1. Antibacterial activity
A series of pyrannocoumarin derivatives bearing spirooxindole
moiety was synthesized via a one-pot three-component reaction
between 4-hydroxycoumarin (32), isatin (172), and malononitrile
(102). The antibacterial activities of the prepared compounds were
evaluated against S. aureus, S. epidermidis, E. coli, P. aeruginosa
(Scheme 37) [147]. The compounds showed good to moderate
antibacterial activity. The presence of halo group (173b, X ¼ Br) on
coumarin ring improved the activity. Also, the length of the R group
had great effect on the MIC of the target compounds. Compound
173g with long-chain alkyl halide-functionalized oxindole exhibi-
ted maximum antibacterial activity (MIC: 62.5 mg/mL) as compared
to the others (MIC value: 125e512 mg/mL) revealing the important
role of the lipophilicity controlling the penetration and activity of
the compounds.
5.12.2. Anticancer activity
The cytotoxic activity of the pyrannocoumarins 173 was also
evaluated against U87 human glioma cells. All the derivatives
showed week to moderate cytotoxic activity. Compounds 173a-
173band 173e showed the same cytotoxic activity (IC50: 78 mM) and
compound 173g was the best active compound (IC50: 39.0 mM), but
lower than carmustine as the standard drug (IC50: 3.9 mg/mL)
(Scheme 37) [148]. It has been suggested that the presence of long
lipophilic moiety could increase the anticancer activity of the
compounds, which could be probably due to the higher hydro-
phobic character of the compounds resulting in the high cellular
uptake.
6. Coumarin-fused unsaturated six-membered rings with two
heteroatoms
6.1. Pyrimidinocoumarin derivatives
Pyrimidine, as a privileged scaffold in a wide range of hetero-
cyclic compounds, showed a broad spectrum of activities including
antimicrobial, anti-viral, anti-inflammatory, antihypertensive, anti-
HIV, and anticancer activities [149]. There are several works
reporting the biological activity of pyrimidines in fused structure,
especially anticancer activity with various mechanisms. Pyr-
imidinocoumarins were widely evaluated as antibacterial, anti-
cancer, antioxidant, and antithrombotic agents (Fig. 39)
[78,148e153].
6.1.1. Anticancer activity
A series of mono- and di-substituted 2-phenyl-benzopyr-
anopyrimidines (PBPP) (176, 178, 179) were synthesized via ternary
condensation of salicylaldehyde (99) or its derivative (174), ECA,
and benzaldehyde (125) in the presence of CH3COONH4 (Scheme
38) [150]. The selectivity of the synthesized compounds to telo-
meric G-quadruplex DNA and their inhibitory effect on telomerase
activity were evaluated. The results showed that the di-substituted
PBPP derivatives (179) with two cationic side chains had higher G-
quadruplex stabilizing property than the monosubstituted de-
rivatives (176 and 178) due to the great impact of two alkylamino
side chains on a strong interaction with G-quadruplex and their
large planar scaffold. The cytotoxic activity of the compounds was
also evaluated against normal cell line (ECV-304) and a series of
telomerase positive cancer cell lines (A549, HepG2, and K562).
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Table 13
Classification of 3,4-heterocyclic fused coumarins based on the structure and biological properties.

C$NO. Chemical structure Biological activity Result Ref.

Coumarin-fused five-membered heterocycle with one heteroatom

18 MDR reversal HCT116/VM46 IC50: 40 mM [28]

19 In vitro Cytotoxic L1210 IC50: 10 mM [28]

27 Anti-retroviral IC50: 8.0 mM [36]

30a Topoisomerase I inhibitor IC50: 38.5 nM [40]

30b DYRK1A inhibitor IC50: 0.07 mM [40]

34 Antifungal Botrytis cinerea EC50: 1.72 mM [43]

37d Anticancer HCT-15 IC50: 8.0 mM [44]

40b Anticancer SK-BR-3 ED50: 0.10 mM [47b]

41 Antioxidant 1.62 times more than trolox [48]

43 Estrogen receptor modulator IC50: 1.03 mM [51]

28
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Table 13 (continued )

C$NO. Chemical structure Biological activity Result Ref.

44 Antifungal F. oxysporum Inhibition Zone: 16 mm [52]

47d Antimicrobial G. candidum Inhibition Zone: 10 mm [52]

51 RNA-binding microRNA-29a [55]

53b Antiproliferative Hela IC50: 8.84 mM [58]

62 Anticancer MCF-7 IC50: 41.0 mM [60]

Antioxidant IC50: 4 mM
Coumarin-fused five-membered heterocycle with two heteroatom
65a Antibacterial MIC: 100 mM [72]

S. aureus and
S. typhi
68 Antibacterial Candida albicans Inhibition Zone: 14 mm [52]

69 Antifungal Candida albicans Inhibition Zone: 10 mm [52]

73a Anticancer A549 IC50: 27.0 mM [76]

77 Anticancer HCT116 IC50: 1.4 mM [80]

(continued on next page)

29
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Table 13 (continued )

C$NO. Chemical structure Biological activity Result Ref.

Coumarin-fused saturated 6-membered heterocycle

80a Antifungal Powdery mildew 68% [82]

86 Antipsychotic Ki: 1.5 nM [83]

(Dopamine D4 receptor antagonists)

87a Bronchodilator ID50: 35 mg/kg [84]

90e Antimicrobial genomic cleavage [90]

S. aureus and
A. niger
Coumarin-fused unsaturated 6-membered heterocycle with one heteroatoms
93f Antimicrobial MIC: 62.5 mM [93]

S. aureus and E. coli

96g Antibacterial Inhibition Zone: 22 mm [91]

B. subtilis and E. coli

100a Antibacterial MIC: 6.3 mM [95]

S. epidermidis

30
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Table 13 (continued )

C$NO. Chemical structure Biological activity Result Ref.

103d Anti-inflammatory 62% [96]

Analgesic
106 Antimalarial plasmodium falciparum IC50: 1100 nM [97]

112 Anticancer EAC IC50: 0.12 mM [98]

113 Anticancer EAC IC50: 0.12 mM [98]

114 Anticancer EAC IC50: 0.13 mM [98]

115 Anticancer EAC IC50: 0.13 mM [98]

121 Anticancer EAC IC50: 245.7 mM [105]

123 Anticancer MDA-MB IC50: 8e16 mM [108]

126a Anticancer IC50 against A-549: 0.14 mM [109]

129a Anticancer A-549 IC50: 0.14 mM [110]

(continued on next page)

31
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Table 13 (continued )

C$NO. Chemical structure Biological activity Result Ref.

132 Antimicrobial MIC: 50 mg/mL [112]

B. subtilis, S. aureus, E. coli, and A. niger

135a Anti-inflammatory 89% [122]

Antimicrobial
Pseudomonas chinchori, Aspergillus fumigatus MIC: 25 mM
and and
Penicillium wortmanni MIC: 100 mM
141c Anticholinesterase AChE IC50: 0.038 mM [125]

142 Anticancer MCF-7 IC50: 49 mM [127]

146 Antibacterial S.aureus, E.coli and S.typhi MIC: 150 mM and 100 mM [130]

152 Antibacterial E.coli MIC: 105 mM [131]

155 Antibacterial S.typhi MIC: 50 mM [72]

158 Antibacterial EC50: 0.141 and 0.115 mM [132]

B. cinerea and C. capsica

32
F. Salehian, H. Nadri, L. Jalili-Baleh et al. European Journal of Medicinal Chemistry xxx (xxxx) xxx

Table 13 (continued )

C$NO. Chemical structure Biological activity Result Ref.

162a Anticholinesterase AChE IC50: 5.0 nM [138]

165 Antibacterial MIC: 15 mM [140]

Bacillus subtilis
167a Antibacterial Bacillus subtilis Inhibition zone: 22 mm [140]

Antifungal Aspergillus niger Inhibition zone: 14 mm

170d Antibacterial S. marcescens Inhibition zone: 25 mm [142]

171 Antimicrobial chrysogenum Thom, chrysogenum Thom and Aspergillus ochraceus Inhibition zone: 22 mm [143]

Wilhelm and 20 mm
173 Antibacterial U87 IC50: 39 mM [147,148]

Anticancer
Coumarin-fused unsaturated 6-membered heterocycle with two heteroatoms
179 Anticancer HepG2 IC50: 2.1 mM [150]

181 Anticancer HepG2 IC50: 18.8 mM [150]

187c Anticancer U46619 HepG2 IC50: 3.0 mM [152]

(continued on next page)

33
F. Salehian, H. Nadri, L. Jalili-Baleh et al.
Table 13 (continued )
C$NO. Chemical structure Biological activity
188 Antibacterial S. aureus
194 Antimicrobial C. albicans, S. aureus
Antioxidant
198b Anticancer
200 Anticancer
Coumarin-fused 7-membered heterocycle
203c Anticancer
Antioxidant
Telomerase inhibition activity of the derivatives and their effect on
the cancer cell lines revealed that compound 179 was the most
promising one as a telomerase inhibitor and telomeric G-quad-
ruplex binding ligand and had significant selectivity over normal
cells (IC50: 2.10 and 15.5 mM against HepG2 and normal cell lines,
respectively). Additionally, cellular experiments displayed a
notable decrease in the cell population growth as well as a short-
ening of the telomere length. It was also found that compound 179
accelerated the senescence of K562 cancer cell lines.
A pyrimidine-fused coumarin derivative was constructed form
the acetylation of 2-amino-5-bromo-4-hydroxxy-5H-chromeno-
[4,3-d]-pyrimidine-5-one 180 (Scheme 39) [151]. The molecules
have been evaluated as anticancer agents against HepG2 cell line.
Results revealed that compound 181 had higher cytotoxic activity
(IC50: 18.80 mg) compared to compound 180.
6.1.2. Antithrombotic activity
Pyrimidinocoumarin was reported as antiplatelet and antith-
rombotic compounds [152]. Compounds 183a-c were obtained by
oxidation of compound 182 with KMnO4 (Scheme 40) [152].
Compounds 185a-f were synthesized from the reaction of com-
pound 184 (R’ ¼ CN) with amidine or guanidine in ethanol and
compounds 186a-c were prepared via a three-step reaction
including (1) reaction between compound 184 (R’ ¼ COOCH3) and
S-methylisothiourea, (2) chlorination with POCl3, and (3) replace-
ment of chlorine with cycloamine. Also, oxidation of the SCH 3
group of compounds 186a-c with m-chloroperbenzoic acid pro-
duced compounds 187a-c. Inhibition of the platelet aggregation
and clot retraction of compounds 183e187 were studied using ADP-
, arachidonic acid-, and the stable TXA2-receptor agonist U46619-
induced platelet aggregation in rabbit platelet-rich plasma and
against thrombin-induced clot retraction in rat-platelet-rich
plasma. Some of the compounds exhibited broad-spectrum of an-
tiplatelet activity in vitro against ADP- AA- and U46619-induced
aggregation and had higher potency in comparison with aspirin
34
European Journal of Medicinal Chemistry xxx (xxxx) xxx
Result Ref.
MIC: 100 mM [72]
Inhibition zone: 19 mm [153]
4 times more than vitamin E
HepG2 IC50: 36.0 mM [151]
HepG2 IC50: 58.0 mM [151]
HepG2 IC50: 0.29 mM [158]
IC50: 0.29 mM (DPPH assay)
as the standard antithrombotic drug. Also, the results showed that
the presence of any substituents (except for R’ ¼ SO2CH3) at posi-
tion 2 of the pyrimidine ring resulted in the lower fibrin clotting
retraction and also antiplatelet activity than the unsubstituted
analogue (Up to 1 mM, Table 12). Furthermore, it was cleared that
in vivo antithrombotic activity had no relation with in vitro inhi-
bition of platelet. Only compounds 183d and 187aec could signif-
icantly prevent the thromboembolic paralysis and they were more
potent than aspirin; but less powerful than the conventional anti-
coagulant warfarin. Compound 187c displayed 3 times more potent
activity than compounds 187a and 187b.
6.1.3. Antibacterial activity
A series of pyrimidine-fused coumarin derivatives (188) was
prepared from compound 63a via a two-step reaction and their
antibacterial activities was evaluated against Gram-positive
(S. aureus) and Gram-negative bacteria (S. typhi) (Scheme 41)
[78]. All compounds 188 showed similar activity against S. aureus
(MIC value of 100 mg/mL), but the order of antibacterial activity
against S. typhi was X ¼ O > NH > S.
Also, a series of pyrimidine-annulated coumarins (190e196)
were synthesized by reaction between 3-cyano-4-chlorocoumarin
(184a) and heteroarylamine (189) in one pot condition and then
they were evaluated as antimicrobial agents using the disk diffu-
sion method (Scheme 42) [153]. The reduction in bacterial growth
was observed for all the compounds except for compounds 195 and
196. Just compound 195 showed fungistatic activity against A. niger
(growth inhibition zone: 15.0 mm), as potent as the standard
antibiotic nystastin (growth inhibition zone: 17.0 mm). Compound
194 exhibited strong antimicrobial activity against various infec-
tious microorganisms including E. coli, K. pneumoniae, P. aeruginosa,
S. aureus, S. enteritidis, A. niger, C. albicans and P. aeruginosa without
any selectivity (growth inhibition zone: 17.0, 18.0, 19.0, 18.0, 16.0,
19.0, and 16.0 mm, respectively).
F. Salehian, H. Nadri, L. Jalili-Baleh et al.
6.1.4. Antioxidant activity
The antioxidant capacity of compounds 190e196 was also
determined spectrophotometrically using phosphomolybdenum
method. Compound 194 showed four times more activity than that
of the standard drug a-tocopherol acetate (Fig. 42) [153]. The de-
gree of antioxidant capacity, in descending order, was 194 > 195 >
196 > 193 > 190 > 189 > 192. After hydrolysis of compounds 190
and 192 producing compounds 191 and 193, respectively, the
antioxidant activity was increased (193 > 192 and 191 > 190) which
could be due to the higher ability of the compounds in the acidic H-
atom transfer.
6.2. Imidazopyrimidinocoumarin derivatives
Imidazo[1,2-a]pyrimidines have attracted a great deal of interest
among researchers in the field of medicinal chemistry because of
their broad spectrum of biological activities such as antimicrobial,
antifungal, antiviral, anticancer, anti-tubercular, anti-inflammatory,
parasiticidal, benzodiazepine receptor stimulating, calcium chan-
nel blocking, and P38 MAP kinase inhibitory activities [154]. Imi-
dazopyrimidinocoumarins are tetracyclic fused heterocycles with
anticancer activity (Fig. 40) [151].
6.2.1. Anticancer activity
The cyclization of compound 180 by 4-substituted phenacyl
bromide 197 yielded imidazopyrimidinocoumarin 198. Compound
198a showed more cytotoxic activity than compound 198b. The
order of toxicity against HePG2 cell line was 198a>198b (Scheme
43) [151].
6.3. Pyrimidopyrimidinocoumarin derivatives
Pyrimido[1,2-a]pyrimidines are one of the famous scaffold in
various therapeutically potential compounds like bronchodilator,
vasodilator, anticancer, and anti-hypertensive agents [155]. The
effect of the annulation of this heterocyclic ring with coumarin
scaffold on the biological properties of the target compounds was
evaluated. It was found that pyramidopyrimidinocoumarins could
be considered as potential antitumor agents (Fig. 41) [151].
6.3.1. Anticancer activity
Sherif et al. synthesized compound 201 as a pyrimidopyr-
imidinocoumarin derivative from the cyclization of the compound
180a with methyl acrylate (199) and assessed its anticancer activity
against HePG2 cancer cell lines (Scheme 44) [151]. The results
showed that the activity of compound 200 did not significantly
change compared to compound 180a. Comparison of the cytotoxic
activity of all the compounds prepared in the study performed by
Sherif et al. revealed that order of the cytotoxic activity was 181b
[ 198a>200 > 198b confirming the important role of the type of
the heterocycle fused at 3,4-positions of the coumarin ring.
7. Coumarin fused seven-membered ring
7.1. Thiazepinocoumarin
Thiazepine and its derivatives are pharmacologically important
compounds having various biological properties such as anticancer
and anti-inflammatory effect [156]. The aryl- and heteroaryl-fused
1,4-thiazepines are privileged structure with fascinating pharma-
cological properties, such as calcium channel blocking, antipsy-
chotic, anti-inflammatory, antibacterial and antiviral activities
[157]. There is only one report about thiazepine-fused coumarin
derivatives as anticancer and antioxidant agents (Fig. 42) [158].
35
European Journal of Medicinal Chemistry xxx (xxxx) xxx
7.1.1. Anticancer and antioxidant activities
Our group prepared a series of thiazepine-annulated coumarins
(203) from 4-hydroxycoumarin derivatives (32) [158]. The in-
termediates (201) were reacted with 2-aminoethanethiol hydro-
chloride (202) to yield compounds 203 (Scheme 45). The
antioxidant and cytotoxic activities of the thiazepine-fused cou-
marins were evaluated. Compounds 203a and 203b showed the
highest antioxidant power determined using the DPPH colorimetric
method (IC50: 0.12 mM), but the activity was lower than quercetin
as a standard drug (IC50: 7.92 mM). The study revealed that thia-
zepine annulation improved the radical scavenging ability of the
mother compounds. Compound 203c with respectable DPPH
radical scavenging activity (IC50: 0.29 mM) exhibited the most
potent scavenging activity confirmed by FRAP assay (FRAP
value ¼ 186.4 mM Fe2þ/100 mg), more potent than quercetin (FRAP
value ¼ 53.9 mM Fe2þ/100 mg). Moreover, the result of cytotoxic
evaluation displayed that all derivatives of compound 201 had no
significant cytotoxic activity against all the tested cell lines; while
fusing of thiazepine ring at 3 and 4 positions of the coumarin ring
resulted in the formation of hybrid structures having good cyto-
toxic activity against all the tested cell lines. Compound 203c was at
least two times stronger than etoposide as a standard drug against
human cancer cell lines such as SK-N-MC, MDA-MB 231, and MCF-7.
8. Conclusion
Coumarins are the heterocyclic structures currently being of
great interest in the development of new lead structures bearing
valuable biological properties. In this work, we try to review the
effect of the heterocycles annulation at 3,4-position of the
coumarin ring on the biological activity of the target structures.
This review provides a better insight into medicinal chemists on the
potential biologically active heterocyclic-fused coumarin de-
rivatives to design new coumarin analogs with a more significant
therapeutic effect. So, it will help in understanding the effect of
various substituents and heterocyclic rings fused to 3,4-position of
coumarin on the biological activities of the target compounds. The
biological properties of different 3,4-heterocyclic-fused coumarins
along with chemical structures are schematically reviewed in
Table 13.
All studied activities like antibacterial, antifungal, anticancer,
anti-proliferative, antipsychotic, antimalarial, antithrombotic, es-
trogen receptor modulating, RNA-binding, antioxidant, and
DYRK1A inhibitor have been discussed hereunder separated
headings. Antibacterial and antifungal activities were the most
studied analyses performed on the heterocycles fused to 3 and 4
positions of the coumarin ring. Heterocyclic rings annulation at 3
and 4 positions of coumarin ring generally produced an improved
synergistic effect. It has been revealed that the antimicrobial ac-
tivity of the heterocyclic fused-coumarins could be efficiently
modulated by the pattern of appropriate substitutions. The pres-
ence of the fused cyclic skeleton like 7,8-benzo substituent on the
coumarin ring could improve the potent antibacterial activity of the
target compounds; while, omitting or protection of the free amine
groups caused deterioration of the antimicrobial activity. Lip-
ophilicity also played a crucial role on the antimicrobial activity of
the target compounds through improved permeation of the target
compounds. Some of the studies suffered from lack of the deriva-
tization limiting the appropriate QSAR and more studies are
necessary to comprehensively understand the antimicrobial
mechanism of the 3,4-heterocycle-fused coumarins.
The anticancer effect was another most studied biological ac-
tivity. Table 13 shows the structure of all the heterocycles fused to
3,4-position of the coumarin ring with anticancer potency. Pyrrole,
furan, thiophene, benzofuran, selenophene, pyrazole,
F. Salehian, H. Nadri, L. Jalili-Baleh et al.
hydroimidazole, pyridine, hydropyridine, pyran, spiroxindole, py-
rimidine and thiazepine are heterocycles fused at 3,4-position of
the coumarin rings. Pyrimidine derivatives, especially amino-
pyrimidine showed great potential to endow the target compounds
with remarkable cytotoxic activity. Lipophilic substituents on spi-
rooxindol, pyran and imidazole moieties fused to the coumarin ring
increased anticancer activity of the target structures. In furo-
coumarin derivatives, the alkoxy and hydroxyl enriched com-
pounds had better potency compared with alkyl analogs. Moreover,
fluorine group as the unique electron-withdrawing group (F)
showed more effect on the cytotoxic activity of the quinolinocou-
marin derivatives than Cl, OMe, or Me substituents. Also,
hydroxamic acid and ureido groups could improve the cytotoxic
activity of the thienocoumarin derivatives. There are still gaps in
the anticancer mechanism of various reported 3,4-heterocycle-
fused coumarins and more studies should be performed to ratio-
nally design appropriate target structures.
Indolocoumarins, pyrano- and pyranoquinolinocoumarins were
the only 3,4-heterocycle-fused coumarin scaffolds studied in
neurodegenerative diseases. Pyrano- or pyranoquinolinocoumarins
showed appropriate ChE inhibition activity and promising features
to be candidate molecules for further studies as anti-Alzheimer’s
disease agents.
3,4-Furano, seleno, thiazepino, pyridino, and benzofurano-fused
coumarins were studied as antioxidant and anti-inflammatory
agents so far. The compounds bearing hydroxyl, alkoxy, pyridyl or
aminopyridyl groups showed great potential as promising
antioxidants.
In sum, the synthetic methods, biological properties and SAR
studies were discussed in this review to pave the way for further
rational development of heterocycle-fused coumarins. There are
still various type of the reported 3,4-heterocycle-fused coumarins
that no study has been performed on their biological activities.
Moreover, coumarin scaffold could be easily functionalized at 3 and
4 positions providing appropriate condition for annulation with
other heterocycles. Unsaturated bond in lactone ring of the
coumarin ring is also ideal for direct annulation with various het-
erocycles via CeH activation without prefunctionalization pro-
ducing new coumarin-based derivatives which could have probably
significant biological activity. This review tries to open a new ho-
rizon for research on 3,4-heterocycle-fused coumarins and to
encourage medicinal chemists to use the promising heterocycle-
fused coumarins for further biological studies.
Funding
Funding was received for this work.
All of the sources of funding for the work described in this
publication are acknowledged below:
Research ethics
We further confirm that any aspect of the work covered in this
manuscript that has involved human patients has been conducted
with the ethical approval of all relevant bodies and that such ap-
provals are acknowledged within the manuscript.
Declaration of competing interest
We wish to confirm that there are no known conflicts of interest
associated with this publication and there has been no significant
financial support for this work that could have influenced its
outcome.
36
European Journal of Medicinal Chemistry xxx (xxxx) xxx
Acknowledgement
The authors thank The Institute of Pharmaceutical Sciences
(TIPS).
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