Review on Chromen derivatives and their Pharmacological Activities
Ravi Kant Kushwaha1,2, Kuldeep Singh*1, Piyush Kumar1, Dinesh Chandra2
1Faculty of Pharmacy, Integral University, Lucknow-226026, Uttar Pradesh, India.
2Faculty of Pharmacy, GCRG College of Pharmacy, BKT Lucknow-226201, (U.P.), India.
*Corresponding Author E-mail: kuldeep@iul.ac.in
ABSTRACT:
Chromens are naturally occurring or synthetically obtaining compounds and these are oxygen containing heterocycles, abundantly found in nature in the form of flavone, isoflavones, flavanones, catechins, anthocyanins and collectively known as flavonoids and isoflavonoids. A large number of synthetic analogues of chromenones have been evaluated for their anticancer, anticonvulsant, angioprotective, antiallergic, antihistaminic, antimicrobial, antioxidant, anti-HIV etc activity. A variety of cellular targets (receptors) are interacting with the derivatives of benzopyran moiety and that can be responsible for their wide ranging biological activities. The motive of the present paper on chromen and there derivatives was to review the available information on this field.
KEYWORDS: Chromenes, flavonoids, anticonvulsants, Benzopyran, Anticonvulsant.
INTRODUCTION:
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 2H-chromens are shown below- [3]
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-
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]
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-
1. Chromen derivative as Antimicrobial:
Antimicrobials are the drugs which are use to kill or inhibit the growth of micro-organism.[9-14,61] 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-ve organisms Escherichia coli & Pseudomonas aeruginosa.[15]
(12E)-N-((7-methyl-4-methylene-4H-chromen-3-yl)methylene)-4-nitrobenzenamine
(1Z)-1-((7-methyl-4-methylene-4H-chromen-3-yl)methylene)thiosemicarbazide
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 in females. Oral contraceptives are the combinations of estrogen and progestin. These drugs are inhibiting the release of eggs from the ovaries. 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 known as mini pill.[16-19]
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-dimethyl-3-phenyl-4-[4-(2 pyrrolidinoethoxy) phenyl] chroman hydrochloride.
1-(2-(4-(7-methoxy- 2, 2-dimethyl-3-phenyl-2H-chroman-4-yl)phenoxy)ethyl)pyrrolidine
Fig. 2.1 Ormeloxifene
3. As antiepileptic
Epilepsy is a common neurological disorder affecting approximately 45100 million people globally. Though many antiepileptic drugs are available in clinical use, neurotoxicity and distinctive adverse effects restrict their clinical use. Therefore, it is necessary to discover new chemical pharmacophores as more effective antiepileptics with less neurotoxicity.[20-22]
3.1 Azolylchroman derivatives were prepared as conformationally work as analogs of (arylalkyl)azole anticonvulsants. The anticonvulsant activities of the Azolylchroman derivatives are evaluated by pentylenetetrazole (PTZ)-induced convulsions in mice by determining seizure latency and protective effect. Among these compounds, 7-chloro-3-(1H-imidazol-1-yl)chroman-4-one and 3-(1H-1,2,4-triazol-1-yl)chroman-4-one exhibited significant action in decrease seizures and also effective against PTZ-induced seizures.
3.2 If the Schiff base is present in chroman nucleus, causes increase in antiepileptic activity. There is following examples of Schiff base with chomen nucleous.
Similarly isatin being associated with a Schiff base accounts for its antiepileptic activity.
3.3 P.M. Ronald et al. synthesized derivatives of coumarins and these derivatives reported earlier for anti-anxiety, anti-convulsant activity. Some Benzopyran-2-one derivatives reported Anti-convulsant activity described by KOTI et al. PT2 induced seizure model in mice.
4. As Anti-inflammatory and analgesic:
4.1 Inflammation is the first response of the immune system to infection, irritation or foreign substance. 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:[23-26,59-60]
4.2 Inflammatory stimuli stimulate to secrete pro-inflammatory cytokine Factor α. Factor α is also known as TNF α and is responsible for the tumor Necrosis.
Chroman molecule blocks the secretion of TNF α production. It is found that in chroman moiety the substitution in benzene ring increases the ability to block Factor α or TNF α production as response to inflammatory stimuli. The methoxy group present at 7th position and 3,4,5-trimethoxy phenyl group in chromen are very potent blockers of TNF α production. For example the compound 7-methoxy-2-(2,4,5-trimethoxyphenyl)-2H-chromene shows the good activity against the TNF α production.
4.3 Novel Schiff' base-containing a 7-amino-4-methylcoumarin moiety synthesized by Pradeep kumar Ronad and Satyanarayan Dharbamalla et al. The synthesized compound were tested for Anti-inflammatory activity and Analgesic activity. The compound 7-(substituted benzylideneamino)-4-methyl-2H-chromen-2-one derivatives shows good activity and found more potent than to the reference drug. Examples:
4.4 The compound 4-chloro-2,2-dialkyl chromene-3-carbaldehyde chromen derivatives in condensed form shows good anti-inflamatory activity and thiosemicarbazide substitution at the position 3rd increases plasma drug concentration(PDC) of the compound. The compound 1-(4-chloro-2,2-dimethyl-2H-chromen-3-yl)methylene] thiosemicarbazide is good anti-inflamatory and have the better activity as compare to standard indomethacin.
5. As dopamine antagonist:
A dopamine antagonist is also known as antidopaminergic drug. Antidopaminergic drugs cause receptor antagonism by blocking dopamine receptors. Generally antipsychotic drugs are dopamine antagonists and use in treating schizophrenia, bipolar disorder and some other antidopaminergic drugs are use for treatment of nausea and vomiting and also use as antiemetic. A series of chromen-2-one discovered with selective affinity for the dopamine (DA) D4 receptor is described. The target compounds were tested for binding to cloned human DA D2l, D3, and D4 receptor subtypes expressed in Chinese hamster ovary K1 cells. The compound 7-[(2-phenylaminoethylamino) methyl]chromen-2-one is responsible for accumulation of rat brains at dose given 20 mg/kg orally. Because it causes increased DOPA (l-3,4-dihydroxyphenylalanine) level in rat brain.[27]
6. TRPM8 antagonists (Transient Receptor Potential Melastatin 8):
TRPM8 is a member of transient receptor potential ion channels family and M stands for melastatin. TRPM family consists of eight different channels TRPM1 to TRPM8. These channels have different-different work. The TRPM channels regulates calcium oscillations after T cell activation by TRPM4, Modulation of insulin secretion and sensory transduction in taste cells regulated by TRPM5, TRPM8 regulates Cold sensation, Heat sensation, TRPM3 is responsible for inflammatory pain and Regulation of magnesium reabsorption in the kidneys, TRPM6 responsible for absorption in the intestines and Regulation of cell adhesion by TRPM7.
Chaudhari, Sachin S.Kadam et al. synthesized N-aryl-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxamides and it is found that the synthesized compound is active against TRPM8 channel antagonism. With the help of SAR study the effects of functional groups on 4th position of the chromene ring was found interesting results. The 4-hydroxy derivatives showed excellent potency and selectivity.[28-29]
7. Anticancer Activity Of Chromene:
The disease cancer is characterize by uncontrolled growth of abnormal cell and causes second highest mortality in the world. Todays 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. [30-36]
7.1 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.
7.2 A novel class of microtubule inhibitors belongs to Substituted 4-aryl-4Hchromene compounds. Substitution of aryl group at the 4th position increases the anticancer activity of the compound.
7.3 2,3-diaryl chromanones derivatives was synthesized under microwave irradiation technique and synthesized compound was evaluated for their cytotoxicity using MTT(3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) assay using HL60 cells and Peripheral blood mononuclear cells (PBMC). Lipid peroxidation assay was use for antioxidant activity.
7.4 A series of newly synthesized compounds N-substituted-3-(2-oxo-2H-chroman-6-ylimino)thioureas, N-substituted-3-(2-oxo-2H-chroman-6-ylimino)thiazolidin-4-ones was prepared and the activity of compound was tested against PTZ and strychnine induced convulsion. The newly synthesized compound shows good anticonvulsant activity.
8. Aldose reductase inhibitor:
Aldose reductase is an enzyme and is present in the body. Aldose reductase enzyme catalyzes sorbitol pathway for the formation of fructose from glucose. Glucose is very important factor in the body for energy processes. The excess of glucose in the body is harmful for health. The compound and derivatives of 4-oxo-4H-chroman-2-carboxilic acid was synthesized and it was found that the synthesized compound has aldose reductase inhibitory activity.[37]
9. Carbonic anhydrase inhibitors:
Carbonic anhydrase is an enzyme and is found in the body. This enzyme regulate the process of inter-conversion of carbon-dioxide and water into carbonic acid, protons and bicarbonate ions in the body. The carbonic anhydrase inhibitors are the class of drug which are inhibit the carbonic anhydrase enzyme present in the body and suppress the formation of carbonic acid, protons and bicarbonate ions. Carbonic anhydrase regulates pH of different parts of the body. The absence or dysfunction of carbonic anhydrase causes diseases like indigestion due to loss of acid production in stomach, kidney failure etc. Carbonic anhydrase inhibitors are used as anti epileptic, anti-glaucoma agents, diuretics etc.
A series of chloro- and methoxy substituted 2-amino-3-phenyl-4H-chromen-4-ones is synthesized and tested for their carbonic anhydrase inhibitory activity. These compounds shows good activity.[38]
10. 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.[39-46]
10.1 Rezayan and co-workers et al. describe synthesis of coumarin & its derivatives and antimycobacterial activity was evaluated by the broth microtiter dilution method invitro against the bateria M. bovis. The activity results are compared with ethambutol. Some of the synthesized derivatives found active against M. bovis.
X=H, R=Isobutyl
10.2 1,3,4-oxadiazole-benzothiazole acetamide derivative was synthesized by Patel and co-workers. The synthesized compound shows anti tubercular activity against the bacteria Mycobacterium tuberculosis (MTB) H37Rv.
N-(4-iodophenyl)-2-((5-2-oxo-2H-chromen-3yl)-1,3,4-oxadiazole-2-yl)sulfanyl) acetamide
10.3 Rashmi Tandon1, Prija Ponnan, Neha Aggarwal et al. synthesized the compound 7-amino-4-methylcoumarin and the antitubercular activity was tested against H37Rv with the help of broth dilution method. The synthesized compound shows good anti-tubercular activity. The compound inhibits the growth of TB bacteria.
10.4 Silvia H Cardoso, Milena B. Barreto et al synthesized the derivatives of compound 2-oxo-2H-chromene-3-carbohydrazide by the refluxing of compound coumarin-3-carboxylateethyl ester with 80% ethanolic solution of hydrazine. Finally aldehyde in ethanol gives the required compound. The synthesized compound screened for anti-tubercular activity and was found the compound shows good anti-tubercular activity.
11. Other activities:
Coumarin and its derivatives have many other useful activities such as antidepressant [47], antioxidant [48], antinociceptive [49], antiasthmatic [50], antiviral [51-52], anti-influenza [53], anti-Alzheimer [54-55], antihyperlipidemic [56], antipyretic [57], anti-HIV [58] activities etc.
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.
ACKNOWLEDGEMENT:
The authors are thankful to the Integral University and GCRG college of Pharmacy for providing facility and suggestion regarding improvement of manuscript. Special thanks to research committee of Integral University for providing MCN Number- IU/R&D/2019-MCN000537.
CONFLICT OF INTEREST:
None.
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Received on 21.05.2019 Modified on 18.07.2019
Accepted on 20.08.2019 © RJPT All right reserved
Research J. Pharm. and Tech. 2019; 12(11):5566-5574.
DOI: 10.5958/0974-360X.2019.00965.X