Synthesis of 2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetamide Based Thiazolidinone Derivatives as Potent Antibacterial and Antifungal Agents

http://www.ejchem.net ISSN: 0973-4945; CODEN ECJHAO E-Journal of Chemistry 2012, 9(4), 2155-2165 Synthesis of 2-(3-methyl-2-oxoquinoxalin-1(2H)yl)acetamide Based Thiazolidinone Derivatives as Potent Antibacterial and Antifungal Agents SHIV KUMARa*, NITIN KUMARb, SUSHMA DRABUc, SUROOR AHMAD KHANd, OZAIR ALAMd, MANAV MALHOTRAe, AND MD. AKRAM MINHAJa a Division of Pharmaceutical Chemistry, Department of Pharmacy, IEC College of Engineering & Technology, Knowledge Park-I, Greater Noida-201306 (India) b Department of Pharmaceutical Technology, Meerut Institute of Engineering & Technology, Meerut-250005, India c Maharaja Surajmal Institute of Pharmacy, Janak Puri, New Delhi-110058, India d Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi-110062, India e Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Ferozpur Road, Moga142001, India Received 17 November 2011; Accepted 15 January 2012 Abstract: Twelve compounds belonging to series 2-(3-methyl-2oxoquinoxalin-1(2H)-yl)-N-[4-oxo-2-(substituted)phenyl-1,3-thiazolidin-3yl]acetamide (5a-l) were synthesized. These compounds were evaluated for their in-vitro antibacterial against E. coli, S. aureus, K. pneumoniae, P.aeruginosa & antifungal activity against C. albicans, A. niger & A. flavus by cup-plate method. Structures of all the newly synthesized compounds were confirmed by elemental analysis, 1H-NMR & FT-IR spectral data interpretation. Compounds 5d & 5h having p-nitrophenyl & ptrifluoromethylphenyl group respectively on 2-position of thiazolidinone ring attached to N-atom of acetamido group on 1-position of 3-methyl-1Hquinoxaline-2-one, were found to be active against all the bacterial & fungal strains under investigation, while compound 5l having p-chlorophenyl on 2position of thiazolidinone nucleus was reported as least active compound against all bacterial & fungal strain under investigation. Keywords: Quinoxaline, Thiazolidinone, Antibacterial, Antifungal. Introduction Nitrogen containing heterocyclic compounds are indispensable structural units for both the chemists & biochemists. Among the various classes of benzene fused six-membered 2156 Shiv Kumar nitrogen containing heterocyclic compounds, quinoxaline derivatives form important classes of pharmacologically active compounds. Quinoxaline ring is a part of various antibiotics such as hinomycin, levomycin, and actinoleutin that are known to inhibit growth of gram positive bacteria and are active against various transplantable tumors. 1-7 Quinoxaline derivatives have also been found to be associated with a wide variety of biological activities including antifungal8-10, antibacterial10-14, antitubercular8,9,15-18, anti-inflammatory agents19. Further hydrazinoquinoxalines & their cyclic analogues have been reported as antimicrobial agents20. Five member nitrogen & sulphur containing thiazolidinone ring attached with other heterocyclic system have also been found to be associated with wide spectrum of pharmacological activities viz. antibacterial21,22,25,26, antifungal22, anti-inflammatory23, antitumor24, anti-HIV25, etc. Keeping the above facts in view, it was thought worthwhile to design the synthesis of compound series viz. 2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)-N-[4-oxo-2(substituted)phenyl-1,3-thiazolidin-3-yl]acetamide (5a-l) wherein thiazolidinone rings have been attached to quinoxaline at 1 position with an acetamido amino linkage. All the synthesized have been screened for in-vitro antibacterial activity against gram positive bacteria Staphylococcus aureus (ATCC2913), gram negative bacteria Klebsella pneumoniae (ATCC700603), Pseudomonas aeruginosa (ATCC27853), Escherichia coli (ATCC25922) & antifungal activity against Candida albicans (MTCC3017), Aspergillus niger (MTCC281) and Aspergillus flavus (MTCC222) by using cup-plate method. Experimental General Melting points were determined in open capillary tubes in a Hicon melting point apparatus and are uncorrected. All the Fourier Transform-Infra Red (FT-IR) spectra were recorded in KBr pellets on a Shimadzu-8400S spectrometer. The 1H- NMR spectra were taken on a Bruker-Spectrospin DCX (300 MHz) NMR spectrometer. Chemical shifts (δ) are expressed in ppm relative to tetramethylsilane (TMS), used as an internal standard. The purity of the compounds was checked by thin layer chromatography (TLC) on Merck Silica Gel 60F254 precoated sheets. Iodine chamber and UV lamp were used for the visualization of TLC spots. General procedure for the synthesis of titled compounds 3-Methyl-1H-quinoxaline-2-one (1): Pyruvic acid (0.1 mol) and o-phenylenediamine (0.1 mol), in 20% HCl (100 ml), were mixed properly and heated at 45 oC with continuous stirring for about 5 hours. Product was filtered, dried and washed with water, dried and then purified by dissolving in 5% w/v NaOH (75 ml). Then, liquid was filtered and cooled to temperature below 5oC and acidified with glacial acetic acid to pH 6. Buff colored crystals appeared & then recrystallized with dimethylformamide (DMF). Pale yellow crystals, yield 60%, Rf (Ethylacetate : Hexane = 7 : 3) 0.73, m.p. 230oC, 1H-NMR (DMSO-d6, 300 MHz, δ ppm) : 7.624-7.651 (d, 1H, quinoxaline ring protons, J = 8.1 Hz), 7.391-7.441 (t, 1H, quinoxaline ring protons, J = 5.4-9.6 Hz), 7.188-7.250 (m, 2H, quinoxaline ring protons, J = 2.7-7.5 Hz), 2.364 (s, 3H, CH3), 9.1 (s, 1H, NHCO); IR (KBr, cm-1): 762 (ortho-disubstituted aromatic ring), 1390 (C-N), 1500 (aromatic C=C), 1544 (-NH), 1688 (>C=O), 3314 (-NH). Ethyl-[3-methyl-2-oxo-quinoxaline-1-yl]acetate (2): Compound (1) (0.0642 mol), ethylchloroacetate (0.077 mol) and potassium carbonate (0.078 mol) were taken in round bottom flask and refluxed in acetone (100 ml) for 6 hours. After completion of reaction, acetone was removed by reduced pressure. The residue was added to ice cold water (300 Synthesis of 2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)acetamide 2157 ml), acidified with acetic acid, filtered, washed with cold water, dried and finally recrystallized with ethylacetate. Pale yellow crystals, yield 45%, Rf (Ethylacetate : Hexane = 7 : 3) 0.64, m.p. 112oC, 1H-NMR (DMSO-d6, 300 MHz, δ ppm) : 7.739-7.766 (d, 1H, quinoxaline ring protons, J = 8.1 Hz), 7.532-7.559 (t, 1H, quinoxaline ring protons, J = 3.9-4.2 Hz), 7.4367.46 (d, 1H, quinoxaline ring protons, J = 3 Hz), 7.314-7.364 (t, 1H, quinoxaline ring protons, J = 6.6-8.4 Hz), 4.118-4.189 (q, 2H, CH2OCO), 3.386 (s, 2H, CH2CO), 2.397 (s, 3H, CH3), 1.149-1.196 (t, 3H, CH3); IR (KBr, cm-1): 763 (ortho-disubstituted aromatic ring), 962 (aromatic =C-H, bend), 1199 (=C-N), 1285 (C-O, coupled with H-C-H), 1380 (C-N), 1645 (CH=N), 1750 (>C=O), 2745 (C-C). 3-Methyl-2-oxo-quinoxaline-1(2H)-acetohydrazide (3): Compound 2 (0.02 mol) and hydrazine hydrate (0.03 mol) were dissolved in ethanol (50 ml) and refluxed for 6 hours. Reaction mixture was kept in deep freezer for overnight. Product was filtered, dried and finall (...truncated)