Introduction Chapter1.

2024
INTRODUCTION:
[1]
Chromens are obtained from both natural sources and synthesized chemically in laboratory.
Chromens are oxygen containing hetero-cycle fused with benzene ring, abundantly found in
nature in the form of flavone, isoflavones, flavanones, catechins, anthocyanins collectively
known as flavonoids and isoflavonoids and named as chromene. Chromens are found in
sufficient level in bark oil of cinnamon, essential oil, oil of cassia leaf and lavender oil etc. [2]

Chemistry of 2H-Chromenes:
Chromens contain benzopyran ring. Benzopyran is a heterocyclic organic compound well known
as Chromenes that is obtained by fusion of pyran ring containing oxygen as hetero atom with
benzene ring. In IUPAC nomenclature system it is named as chromenes. The two isomers of
chromens are available 1- benzopyran and other second one is 2-benzopyran that varies by the
fusion of two rings benzene and pyran by the orientation compared to oxygen, the location of
oxygen atom is denoted by the number like standard naphthalene nomenclature. The structural
isomers of 2Hchromens are shown below- [3]

O
O

[Figure No-1.1] 2H-chromene [Figure No-1.2] 1H-isochromene

The radical form of chromene is paramagnetic and the unpaired electron is delocalized over the
whole chromene molecule. Chromene is partially saturated with one hydrogen atom by the
addition of tetrahedral methylene group in the pyran ring. Thus there are number of structural
different isomers are possible because of multiple locations are possible of oxygen atom and
tetrahedral carbon.
Saturated chromene is called as chroman(3,4-dihydro- 2H-chromene). Chroman is an aromatic
bicyclic heterocycle. Its molecular formula is C9H10O and chromen have molecular weight
is about 134.18 and chemical structure shown below-

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 Introduction Chapter1. 2024
8 1

7 O 2

3
6
5 4

[Figure No-1.3] 2H-chromene

Chroman derivatives are reported for many useful biological activities such as antioxidant,
antiestrogen, anticonvulsant, and neuroprotective etc. Chromens are obtained by natural sources
as well as many synthetic methods are also available for the synthesis. Some novel substituted
2H-chromene are selected for research work as these structural units are found in a large
number of drugs and in natural products. [4,5]

Shitara et al and Buyukkidan, Bilgic and Bilgic gives the one step synthesis of Trolox (2,5,7,8-
tetramethyl-6- hydroxychroman-2-carboxilic acid). The reaction mechanism involves hetero-
Diels-Alder reaction of methacrylate with in situ-genrated o-quinone methides. In this method
the reaction of trimethylhydroquinone with paraformaldehyde, dibutylamine, acetic acid, and
excess methyl methacrylate yields of 2 methyl ester. This procedure avoids the use of the high-
pressure conditions.[6] Trolox synthesized commercially by synthetic procedure and it shows very
good water solubility and high degree of antioxidant activity. A wide variety of chromans are
synthesized by using Trolox as initial starting material. [7,8]

O
O
OH

[Figure No-1.4] 2,5,7,8-tetramethyl-6-hydroxychroman- 2-carboxylic acid

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 Pharmacological Activity Chapter 2. 2024

Some Chromen derivatives and pharmacological activities:

Chromens and its analogs are useful and important pharmacophores and special structures in
medicinal chemistry. Chromens having a distinguish attributes of clinically used drugs. It is found
in many recent research work chromen derivatives have broad spectrum of pharmacological
activities. There is some of derivatives and there pharmacological activities are discussed bellow-

2.1 :- Chromen derivative as Antimicrobial:

Antimicrobials are the drugs which are use to kill orinhibit the growth of micro-organism.[9-
10,22]
R.B. Patil et al. synthesized aromatic ketone-antimicrobial by the condensation of 7-
hydroxy-3-formyl chromen-4-one with substituted acetophenones by base catalyzed reaction
followed by dehydration using claisen-schmidt reaction and schiff bases were prepared. The
synthesized Schiff bases and chalcones were tested for their antimicrobial activity on bacteria
Staphylococcus aureus& Bacillus subtilis Gm+ organisms and two Gm-veorganisms
[11]
Escherichia coli & Pseudomonasaeruginosa.

NO2

[Figure No-2.1] (12E)-N-((7-methyl-4-methylene-4H-chromen-3-yl)methylene)-4-

nitrobenzenamine

2.2 :- As oral contraceptive:

Oral contraceptives are the drugs which are administered orally and it is used to prevent
pregnancy in females. Estrogen and progestin are sex hormones secreted infemales.Oral
contraceptives are the combinations of estrogen and progestin. These drugs are inhibiting
the release of eggs from the ovaries.

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 Pharmacological Activity Chapter 2. 2024
Contraceptives changes the lining of the uterus for the inhibition of mucus at the opening of the
uterus called cervix, for prevention of sperm entering. Oral contraceptives are a very effective
birth control method. Oral contraceptives are well knownas mini pill.[12,13]
Ormeloxifene oral contraceptive agent developed by the Indian Central Drug Research Institute
Lucknow, India, a nonsteroidal selective estrogen receptor modulator and once-a-week.
Ormeloxifene oral contraceptives under the brand name shaheli.

Ormeloxifene:
trans-7-methoxy-2,2-dim2H-chromene ethyl-3-phenyl-4-[4-(2 pyrrolidinoethoxy) phenyl]
chroman hydrochloride.

CH3
O O
CH3
CH3

[Figure No-2.2]

1-(2-(4-(7-methoxy-2,2-dimethyl-3-phenyl-2H-chromen-4-yl)phenoxy)ethyl)pyrrolidine 1-(2-(4-
(7-methoxy- 2, 2-dimethyl-3-phenyl-2H-chroman-4- yl)phenoxy)ethyl)pyrrolidine

2.3 :- As Anti-inflammatory and analgesic:

Inflammation is the first response of the immune system to infection, irritation or foreign
substance.

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 Pharmacological Activity Chapter 2. 2024
The chromene pharmacophore represents a novel class of COX-2 selective inhibitors (coxibs) in
non-steroidal anti- inflammatory drugs (NSAIDs) which provide higher potency, efficacy, and
selectivity over the existing coxibs (eg: celecoxib, valdecoxib, rofecoxib, and etoricoxib) for
the treatment of inflammation. The chromene coxib clinical candidates are SD-8381 and SC-
75416. SC-75416 provides a fast onset of action and higher efficacy compared to ibuprofen.
Other examples for chromene cyclooxygenase-2 selective inhibitors:[14,15,20,21]

CH3

F F O

O
ClO

OH

[Figure No-2.3] 6-chloro-2-fluoro-8-methyl-2H-chromene-3-carboxylic acid

2.4 :- Anticancer Activity Of Chromene:

The disease cancer is characterize by uncontrolled growth of abnormal cell and causes second
highest mortality in the world. Today’s scenario programmed cell death induced by cytotoxic
anticancer agents commonly use to treat the cancer.
Chromene moieties have been reported with anticancer activity found in many of the natural
compounds. These compounds are isolated from naturally occurring herbal plants and animal
origin like sea fish etc. [16,17]
Tephrosin(lung cancer), calanone(leukemia and cervical carcinoma), acronycine(lung, colon and
ovary cancer), seselin(skin cancer) are the examples of natural anticancer agents which contains
chromen ring.

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 Pharmacological Activity Chapter 2. 2024

H3C
O

O
CH3 O
OH

O
O O
CH3

CH3

[Figure No-2.4] Tefrosin

2.5 :- Antitubercular Activity:

Tuberculosis (TB) is caused by several species of Mycobacterium (Mycobacterium tuberculosis
complex, which includes Mycobacterium tuberculosis itself, Mycobacterium microti,
Mycobacterium pinnipedii Mycobacterium bovis, Mycobacterium caprae, Mycobacterium
africanum, and Mycobacterium canettii), TB is an acute or chronic infectious disease. Generally
TB infected the lungs but can also attack on the central nervous system, lymphatic system,
circulatory system, genitourinary system, gastrointestinal system, bones, joints, and even the
skin etc.[18,19] Rezayan and co-workers et al. describe synthesis of coumarin & its derivatives
and antimycobacterial activity was evaluated by the broth microtiter dilution activity was
evaluated by the broth microtiter dilution results are compared with ethambutol. Some of
the synthesized derivatives found active against M. bovis.

O NH

OR
X

O O

[Figure No-2.5] X=H, R=Isobutyl

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 Conclusion Chapter 3. 2024

CONCLUSION:
In the modern drug discovery benzopyran (also known as chromene) is an very important
class of pharmacophore. The literature has been given more useful information about the
chromene nucleus as a source of new antimicrobial, Oralcontraceptive, antiepileptic, anti-
inflammatory, analgesics, dopamine antagonist, TRPM8 antagonist, anticancer activity and
aldose reductase inhibitor agents. Many researches indicates that the target interaction of
substituted chromene is very good and the compounds shows a variety of pharmacological
actions with very low toxicity or any harmful action. Now there is very high scope and interest
of researchers to design more useful and potent derivatives of chromene having wide diverse
biological activities.

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 Referrence Chapter 4. 2024

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