Novel Fused Pyridine And

Pyrimidine Derivatives
Presented By: Danyah alweet Al-Alweet
Master student.

Preceptor: Prof. wael Abd El-Hafeez El-Sayed.

Wael A. El-Sayed
Prof., NRC, Cairo, Egypt. Qassim university, KSA

Nov. 25, 2020

 • Define the antimicrobial activities of pyridine and

OBJECTIVES pyrimidine derivatives.

• Review the methods, mechanisms, and results.

• Discuss the microbial activity by the molecular

docking study and pharmacokinetics.

INTRODUCTION
§ Antimicrobials - including antibiotics, antiviral drugs, antifungals, and
antiparasitic drugs - are drugs used to prevent and treat infections that
affect humans, animals, and plants.
§ Antimicrobial resistance appears when bacteria, viruses, fungi, and
parasites change over time, and they become less responsive to drugs,
making infections more difficult to treat and increasing the risk of disease,
severe illness and death spread.
§ Prevelance:

§ As per the World Health Organization (WHO), about 33,000 people die
every year in Europe from antibiotic-resistant infection according to
European data, while in the United States the deaths are estimated at
around 35,000. To combat this, there is a great demand for the expansion
of new alternative antimicrobial agents with potent, safe and lower side
effects in comparison to the commercially clinical treatment drugs [3-6].
§ Pyrimidine and pyridine ring systems are very important classes of compounds
owing to their wide-spectrum of biological activities. Nitrogen aromatic
pyrimidine, pyridine, and their analogs occur in nature and they show
energetic role in the pitch of synthetic heterocyclic chemistry [1]. Such
heterocyclic compounds are extensively used for many applications in
medicinal science. Many of their derivatives are used as antimicrobial [2–10],
antiviral [11–13], antitumr [14–21] and anti-oxidant [22,23] agents in
veterinary medicinal.
§ Chalcone derivatives have invited the attention of medicinal chemists due to
their high potential as chemical sources for designing and developing
promising drugs [24,25].
§ chalcone constituents are central initial ingredients for the synthesis of unlike
units of heterocyclic compounds, for example, pyrimidines, thiophenes, and
pyrazolines, etc. Several of these structures are extremely bioactive and are
extensively used as pharmaceuticals [32–35].
 (A)

§ Example of chalcone derivatives and their

indication: (B)

§ The compound (A) 2,2,4- trimethoxy

chalcone (Diuretic).
§ The compound (B) 6-Fluoro-3,4-dihydroxy-
2',4'-dimethoxy chalcone (Anti-cancer).
§ The compound (C) Dimethylamino-2',5'- (C)
dimethoxy chalcone-4 (Anti-inflammatory). (D)
§ The compound ( D,E,F) Nicotinic acid (as
anticoagulants and vasodilators, anti-TB, RA).
§ (Fig. 1)
(E)
(F)

(Fig.1)
§ Herein, the synthesis of some heterocyclic ring systems incorporated with
the novel fusing pyrimidine and pyridine moieties starting from 1-(furan-2-
yl)-3-(thiophen-2-yl) chalcone and evaluated for their in vitro antimicrobial
activity and ADME properties.(Maha) furthermore, molecular docking
studies using tyrosyl-tRNA synthetase from S. aureus were also explored to
better understand the mechanism action of the most active compounds. (1)
METHODS
§ Conventional method.
§ Microwave irradiation method.
§ Synthesis of chalcone-1(furan-2-yl)-3-(thiophen-2-yl) prop-
2-en-1-one
v Conventional method: KOH (0.16 gm, 3 mmol), was dissolved in
H2O (2.5 ml) and EtOH (10 ml) at room temperature. (0.224 gm, 2
mmol) 2- thiophenecaboxaldhyde (1) was added to the solution.
Then, 2-acetyl furan (2) (0.220 gm, 2 mmol) was added over 10 min.
The mixture was stirred for 5 h at room temperature.
v A solid product was poured into water (ice-cold) and neutralized
with dil. HCl. After neutralization, the solid was filtered, washed
with cold EtOH, dried and recrystallized from ethanol to give
chalcone 4.
RESULTS &
DISCUSSION
Chemistry 3.1. §
Chalcone represent a significant synthetic intermediate candidate,
mainly as a building unit for the construction of several heterocyclic
structures. Starting compound 1-(furan-2-yl)-3-(thiophen-2-yl)
chalcone 4, was prepared as a previously reported method [41,42] by
the Claisen-Schmidt reaction of 2-actylfurane with 2-
thiophenecaboxaldhyde in the presence of catalytic KOH, (Scheme 1).
§ The actions of chalcone 4 towards some primary heteroaryl amines
having NH2 group connected at the α-site respect to the ring nitrogen
(1,3-N, N-nucleophiles) was considered. Consequently, chalcone (4)
used for the synthesis of azolopyrimidines (6), (Scheme 2).

H2O

Schem 2. Reagent and condition: (i) KOH.

 H2 O

4 5

- OH § chalcone (4) react with 5-amino-

1,2,3,4-tetrazole monohydride (5) in
basic condition to afford 4,7-dihydro-
5-(furan-2-yl)-7-(thiopen-2-yl)
[1,2,4,5]tetrazolo[1,5-a] pyrimidine (6).
-H
§ The Mechanism : (schem 3)

Schem 3. The mechanism of Chalcon 4.

§ 3.3. Chemistry

§ The building block 7-amino-3H-imidazo [4,5-b]thieno[3,2-e] pyridine

derivatives 9a,b were prepared from the reaction of 2- methyl-7-phenyl-
3-(pyrimidin-2-yl)-5-thioxo-4,5-dihydro-3H- imidazo [4,5-b]pyridine-6-
carbonitrile (7), with the halogen carbonyl compounds (8a,b) in
ethanolic sodium ethoxide under reflux (Scheme 4).

Schem 4. synthesis of starting compounds 9a,b.

 8a,b.

§ Compound (8a,b) react with (EtOH)

7
then they react with Compound (7),
2- methyl-7-phenyl-3-(pyrimidin-2-yl)-5-
thioxo-4,5-dihydro-3H- imidazo [4,5-
b]pyridine-6-carbonitrile.
§ to afford Compound (9a,b), 7-amino-
3H-imidazo [4,5-b]thieno[3,2-e]
pyridine.
§ (schem 5).

9a,b.

Schem 5. The mechanism of Compound (9a,b).

 § the hydrolysis of compound (9b) in 10% ethanolic
KOH solution afforded after acidification with 10%
HCl, the corresponding imidazo [4,5-b]thieno [3,2-
e]pyridine-6-carboxylic acid derivative (10).
§ The reaction of (9b) with hydrazine hydrate afforded
7-aminoimidazo [4,5-b]thieno [3,2-e]-pyridine-6-
carbohydrazide derivative (11).
§ The structure of hydrazide (11) was compatible
with the spectroscopic data. 1H NMR of 11 revealed
the signals of NH and NH2 and did not reveal any
signals attributed to the ethyl function (Schem 6).

Schem 6. synthesis of Imidazopyridothienopyriinidines.

§ compound 11 reacted with acetylacetone to give the corresponding (imidazo
[4,5-b]thieno [3,2-e]pyridin-6-yl) (3,5-dimethyl-1H-pyrazol-1-yl)-methanone
derivative 12 based on the elemental analyses and spectral data. (Scheme 7).

Ac2 (CH2)/AcOH
11

12

Schem 7. synthesis of compound 12.

 § 3.6. Molecular docking study

§ Molecular Docking is defined as the theoretical

calculations of chemical compounds to discover
their biological properties, which are closely
related to drug design and the possibility of a
chemical compound interacting with biological
proteins arising from diseases.
§ Compound (6) displayed binding-energy of
−13.05 kJ mol-1 arene-cation contact between
thiophene and Arg 75 beside forming one H-
bond with the amino acid residues, hydrogen of
NH group with Asp 72 in distance 3.18 Aْ (11%)
(Fig. 2). ‫ﺑﺣث ﻣﮭﺎ‬

(Fig. 2) Molecular docking study of compound 6.

 § A molecular docking study has been performed
using S. aureus tyrosyl-tRNA synthetase as a
target enzyme, To modulate the antibacterial
activity of the synthesized compounds against K.
pneumoniae.
§ Compounds 10 and 12 differ only by the
substituted groups at position C2 of thiophen-3-
amine ring. The former is substituted with a
carboxylic functional group (COOH), and the
latter with 1-(3,5-dimethyl-1H-pyrazol-1-yl)ethan-
1-one moiety (Fig. 3).

§ These compounds showed very close binding

energies values. ١‫ﺑﺣث‬

(Fig. 3) Molecular docking study of compound 10 and 12.

§ 3.7. Evaluation of antimicrobial activity.

all compounds were indeed capable of halting microbial growth and have
inhibition effects toward evaluated microbial strains.
Antimicrobial susceptibility tests proved that compound 6 have an
antimicrobial activity.
- 10 showed a slightly higher antibacterial activity than 12.

§ 3.8. Minimum inhibitory concentration

To assess the antimicrobial effectiveness and MIC values for each

tested compound against evaluated microbial lineages.
Their pharmacokinetic appraisal additionally revealed
promising druglikeness attributes and ADME properties. (1)

Antimicrobial examinations of the compounds were

performed towards some unsafe pathogenic
microorganisms and most of them demonstrated excellent
to moderate activity, Docking of compound 6 into active site
of DNA gyrase B chain shown binding energy of −13.05 kJ
mol−1 and distance at 3.18 Ao. (M)

The binding interactions of the most active analogues were

performed through molecular docking against Staphylococcus
aureus tyrosyl-tRNA synthetase. Results revealed that the
enhanced activity of compound 10 can be modulated by the
establishment, in 10-tyrosyltRNA synthetase complex, of
hydrogen bond interactions between the lone pair of sulfur atom
of the thiophen-3-amine ring and the hydrogen atom of the
hydroxyl group of TYR 170 of 3.80 Å. These findings suggest that
analogues 10 and 12 can be served as best candidates for
designing and discovering of novel antimicrobial agents. (1).
CONCLUSION
§ Novel families of fused pyridine and permidine derivatives have been
synthesized and characterized by spectral and elementary analyses and were
also evaluated for their antimicrobial properties against some pathogenic
strains. Molecular and pharmacokinetic parameters of the promising active
compounds validated good bioavailability and drug-likeness properties.
Computational docking studies on compounds 6, 10 and 12 displaying the
potent inhibitory effect suggest their good fitting in the active sites of
tyrosyl-tRNA synthetase enzyme via different types of interactions, especially
for 10-tyrosyl- tRNA synthetase complex. This study opens the horizons to
apply these potent leads as new antimicrobial agents for infectious disease.
REFRENCES
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