International Journal of PharmTech Research CODEN (USA): IJPRIF ISSN : 0974-4304 Vol. 3, No.1, pp 386-392, Jan-Mar 2011 Exploring Potential of Quinoxaline Moiety

Ashutosh Kumar Patidar*, M. Jeyakandan, Ashok Kumar Mobiya,G. Selvam

College of Pharmacy, Dr. Shri R.M.S. Institute of Science and Technology, Bhanpura, Dist. Mandsaur, (M.P.) 458775 India *Corres. author: [email protected] Tel.: +919575019972, +919024089745

Abstract: Quinoxaline also called benzopyrazine is a heterocyclic compound containing a ring complex made up of benzene ring and a pyrazine ring has been considered as a wonder nucleus which posses almost all types of biological activities. This diversity in the biological response profile has attracted the attention of many researchers to explore this skeleton to its multiple potential against several activities. Present article is sincere attempt to review history, chemistry, synthesis and applications of quinoxline. Keywords: Quinoxaline, Benzopyrazine, Biological activities.

INTRODUCTION active peptides with quinoxaline analogs can lead to Quinoxaline and its derivatives are important nitrogen new therapeutic agents possessing interesting containing heterocyclic compounds of various anticancer properties24. biologically interesting properties with several pharmaceutical applications. Substituted quinoxalines are an important class of benzoheterocycles, which constitute the building blocks of wide range of N N pharmacologically active compounds having antibacterial1-6 antifungal7-8, anticancer9-11, N antitubercular12, antileishmanial13, antimalarial14-15 and N antidepressant activities16-17. Also, some quinoxalin-2- ones and quinoxaline-2,3-diones have been reported to show antimicrobial18-19, novel, potent antithrombotic20, 2,3-bis(2-pyridyl)-quinoxaline (DPQ) anti-pain and anti-inflammatory21-22 activities. Quinoxaline derivatives constitute the basis of many The quinoxaline is described as a bioisoster of insecticides, fungicides, herbicides, as well as being quinoline, naphthalene, benzothiophene and other important in human health and as receptor antagonists. aromatic rings such as pyridine and pyrazine. Because Although rarely described in nature, synthetic of the similarity between some antitubercular drugs quinoxaline moiety is a part of number of antibiotics and quinoxaline, as well as the presence of the such as echinomycin, levomycin and actinomycin quinoxaline moiety in some broad spectrum which are known to inhibit the growth of Gram- antibiotics, it was hoped that quinoxaline analogs positive bacteria and also active against various would exhibit antitubercular activity23. Some of transplantable tumors. In addition, quinoxaline quinoxaline analogues, such as 2,3-bis(2-pyridyl)- derivatives are reported for their application in dyes, quinoxaline (DPQ) complexed with transition metals efficient electroluminescent materials, organic are of current interest in view of its binding to DNA. semiconductors and DNA cleaving agents25. This may suggest that conjugation of biologically Ashutosh Kumar Patidar et al /Int.J. PharmTech Res.2011,3(1) 387

HISTORY CHEMISTRY Quinoxaline is also called as benzopyrazine. It is Quinoxaline is a low melting solid, m.p 29-30˚C and is heterocyclic compound containing benzene ring and miscible with water. It is weakly basic pKa 0.56. pyrazine ring. Pyrazine are stable, colorless compound Quinoxaline forms salts with acids. Nitration occurs which are soluble in water. Unlike pyridine, they are only under forcing conditions (Conc. HNO3, Oleum, expensive, not readily available and so are seldom 90◦C) to give 5-nitroquinoxaline (1.5%) and 5, 7- used as starting material for synthesis of their dinitro- quinoxaline (24%). derivative. Diazines are fused to benzene ring to form NO quinoxaline. The pyrazine ring system is found in the 2 NO2 N N fungal metabolite aspergillic acid and in dihydro form Conc. HNO , Oleum N in luciferin of several bettles including the fire fly is 3 + responsible for the chemiluminescence of this N N O2N N ostracod. Methoxy pyrazine are very important 1.5% 24% component of aroma of many fruits and vegetable such as Peas and Capsicum peppers and also of wines26. Oxidation of quinoxaline results in the formation of N N the product depending on the nature of the oxidizing agent employed. With alkaline potassium permangnate N N pyrazine 2,3-dicarboxylic acid is formed, while with Benzene Pyrazine Quinoxaline peracid quinoxaline di-N-oxide results27.

COOH alk. KMNO4 N

N COOH N - O O N + N CH3COOH + N O -

SYNTHESIS

Quinoxaline itself is prepared by the reaction of o-phenylenediamine and glyoxal.

O NH2 H N + -H2O NH2 O H N

2-Phenylquinoxaline has been prepared in this manner from phenylacylchloride and o-phenylenediamine27. H

NH2 N CH2Cl + O C H NH2 6 5 N C6H5

Oxi

N

N C6H5 Ashutosh Kumar Patidar et al /Int.J. PharmTech Res.2011,3(1) 388

Several methods for synthesis are available in A facile synthesis of quinoxaline derivatives31 and literature which involves conventional one pot28, and quinoxaline-2, 3-diones as NMDA receptor microwave synthesis methods29-30. One-pot efficient antagonists32 were al so reported. o-Iodoxybenzoic green synthesis of 1,4-dihydro-quinoxaline-2,3-dione acid (IBX), a readily available hypervalent iodine derivatives has reported by potential pharmacophore reagent, was found to be highly effective in synthesis 1,4-dihydro-quinoxaline-2,3-dione has been achieved of quinoxaline derivatives, from 1,2-diketones and o- in a one-pot reaction at room temperature from phenylenediamines at room temperature in very high substituted o-phenylene diamine and oxalic acid under yield31. solvent free conditions by a simple grinding method. R Thermal and powder X-ray diffraction analysis was R carried out for some crystals28. O H N R1 2 N R1 + IBX, HOAc A NH H 2 HO A O RT O RT N O H N + 2 N B NH Grinding R 2 HO O B N O R H

29 Gris J et al has carried out the microwave-assisted Various quinoxaline-2,3-diones32 were synthesized by Hinsberg reaction of quinoxalinone derivatives by rotatory evaporation of 1,2-diamino aromatic reacting o-phenylenediamine or 2,3- compounds in diethyl oxalate at 50-80oC. diaminenaphthalene with a variety of α-ketoacids through enzymatic catalysis or microwave irradiation. R R O NH H NH O O Rotavapor N 2 HO O N O + S. cereviciae + o MW irradiation X 50-80 C NH2 NH O O X N O R O N R 2 H

NH H 2 HO O O S. cereviciae N + NH MW irradiation 33 2 R O N R Gallium (IIII) triflate-catalyzed reactions of phenylene-1,2-diamines and 1,2-diketones produce quinoxalines in excellent to quantitative yields. The Quinoxalines are effectively synthesized in a few min reactions proceed with 1 mol% catalyst in ethanol at by the condensation reaction of o-phenylenediamine room temperature. The catalyst can be recycled for at with α-dicarbonyl compounds in ethanol under least 10 times. microwave irradiation30. High yield, short reaction time, pure products without Attempt to synthesize quinoxaline derivatives at room purification and using only ethanol instead of toxic and temperature using molecular iodine as the catalyst are expensive solvents for isolation of the products, are the present in the literature as reported by several aromatic advantages of this method. as well as aliphatic 1,2-diketones and aromatic 1,2- diamines, such as substituted phenylene diamines, tetra amines were further subjected to condensation using NH 2 O R2 N R2 catalytic amounts of iodine to afford the products in C H OH 34 + 2 5 excellent yield . R1 NH MW 2 O R2 R1 N R2

R N R1 R NH2 O O 1 mol% Ga(OTf)3 + EtOH R1 R1 N R1 NH2 Ashutosh Kumar Patidar et al /Int.J. PharmTech Res.2011,3(1) 389

O NH2 + I2 N O

NH2 o 25 C N

PHARMACOLOGICAL USES OF method. The compounds were taken in Jones QUINOXALINE monophasic mediun using a polyxenic culture of E. Antimicrobial Activity histolytica. Microscopic observations of the culture Antimicrobial agent shows activity against bacteria, were taken after 48 hr incubation at 30o. Most of the fungi, mycobacterium species, called antibacterial, compounds displayed in vitro activity at 50-200 µg/ml antifungal, antituberculer activity respectively. There concentrations. Standard drugs such as Nitroimidazole are various quinoxaline derivatives showing and Diloxanide furoate showed in vitro activity at 2-5 antimicrobial activity. µg/ml concentrations. Ganapaty et.al, 1 has synthesized some novel condensed bridgehead nitrogen heterocycles of Antidepressant Activity quinoxalines. All the condensed systems were Hassan et. al,38 have synthesized 3-benzyl-2- evaluated for antimicrobial activity against the gram- substituted quinoxalines as novel monoamine oxidase positive bacteria Staphyllococus aureus and Bacillus A inhibitors. MAO inhibitors represent a useful tool subtilis, the gram-negative Psudomonas aeruginosa for the treatment of several neurological diseases. and proteus vulgaris, the fungi Aspergillus niger and MAOs are implicated in a large number of the Mycobacterium tuberculosis H37Rv species. neurological disorders such as Parkinson’s disease and Antibacterial and antifungal screening was carried out depression. MAO-A inhibitors are used as by Agar Plate Disc Diffusion method at 100 µg/disc antidepressant and antianxiety drugs. The final conc. The antitubercular screening was performed by compounds were evaluated for their MAO-A Microplate Alamar Blue Assay (MABA) method at inhibitory activity in vitro using serotonin as substrate. 6.25 µg/ml concentration. DMSO was used as solvent. The method depends on the determination of MAO-A Nalidixic acid (100 µg/disc) and Clotrimazole (50 activity of rat liver mitochondria. All compounds µg/disc) were used as standard respectively, for under test were used at a final concentration of 1×10-4 antibacterial and antifungal screening. M. Novel synthesis of thieno[2,3-d]pyrimidines and pyrrolo[3,4-b]quinoxalines were synthesized by Anti Cancer Activity Ammar et. al,35 were tested for their antibacterial Sandra P.39 have synthesized Methyl [4-(substituted 2- activity against Staphyllococcus aureus, Escherichia quinoxalinyloxy) phenyl] acetates and ethyl N-{[4- coli and their antifungal activity against Candida (substituted 2-quinoxalinyloxy) phenyl] acetyl} albicans in DMSO at a concentration of 3mg/mL glutamate analogs of Methotrexate and evaluated for in followed by Cup Diffusion Techniqes. Steptomycin vitro anti cancer activity by bioisosteric replacement. (25 µg) and Mycostatin (30 µg) were used as reference for the antibacterial and antifungal activities, Anti Inflammatory and Antioxidant Activity respectively. Asuncion B.40 synthesized novel ring substituted 3- A series of 6,7-Bis[2-(substituted Phenyl)-4-oxo- phenyl -1- (1, 4-di-N-oxide quinoxaline-2-yl) -2- thiazolidin-3-yl]quinoxaline-2,3-(1H,4H)-diones36 propen-1-one derivatives and of their 4, 5-dihydro- were prepared. All the derivatives were screened for (1H)-pyrazole analogues. Synthesized compounds antitubercular activity. Antitubercular activity of the were evaluated for anti-inflammatory and antioxidant compounds was determined by Micro Plate Alamar activity. The tested compounds inhibit the Blue Assay (MABA) method against H37Rv strains of carrageenan-induced rat paw edema (4.5-56.1%). Mycobacterium tuberculosis at a concentration of 6.250g/ml. DMSO was used as solvent. Isoniazid Anti HIV Activity (0.0250 g/ml) and Rifampicin (0.1250 g/ml) were used Since the human immunodeficiency 1 (HIV-1) was as standards. first confirmed as the causative agent of acquired Venugopalan et. al,37 have shown antiamoebic activity immunodeficiency syndrome (AIDS). These are many of 2,3-diaryl-5,8-dimethoxy- quinoxalines. The in vitro clinical drugs, non-nucleoside reverse transcriptase activity of the compounds against Entamoeba inhibitors, which interact with a specific allosteric non- histolytica was determined by the serial dilution substrate binding site on HIV-1 reverse transcriptase, Ashutosh Kumar Patidar et al /Int.J. PharmTech Res.2011,3(1) 390 have proved to be effective anti-HIV drugs because of synthesis have been attention of the chemists, their high potency, low toxicities, and improved pharmacologists and researchers. The anticancer and pharmacokinetics. Thus, Bailing Xu et al synthesized antidepressant activities are the most encouraging N4 – (hetero) aryl sulfonyl quinoxalinones and their activities for the pharmacists. Also the research on analogs and tested for anti viral activity as HIV-1 antitubercular activity has given positive results. By reverse transcriptase inhibitors. The anti-HIV-1 the present scenario and due to their wide range of activities of all target compounds were evaluated by a applications, these compounds have received a great cell-based HIV-1 replication pharmacological model deal of attention in connection with their synthesis and which was set up by HIV-1 (pNL4-3) core packed with it can be concluded that quinoxaline have a great vesicular stomatitis virus glycoprotein. The level of potential. HIV-1 replication was presented by a reporter gene expression (i.e., luciferase activity) in infected cells. ACKNOWLEDGEMENTS Authors are thankful to Subhash Kumar Sojatia, CONCLUSION President, Late Dr. Shri R.M.S. Foundation, Bhanpura The literature reveals that quinoxaline has diverse (M.P.) for providing all facilities to carry out this biological potential, and the easy synthetic routes for study.

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