alexa Synthesis and Characterization of Some New Thiazolidinedione Derivatives Containing a Coumarin Moiety for their Antibacterial and Antifungal Activities | Open Access Journals
ISSN: 2161-0444
Medicinal Chemistry
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Synthesis and Characterization of Some New Thiazolidinedione Derivatives Containing a Coumarin Moiety for their Antibacterial and Antifungal Activities

Edris Valadbeigi* and Shahram Ghodsi

Department of Chemistry, Faculty of Sciences, Islamic Azad University, Karaj Branch, Karaj, Iran

*Corresponding Author:
Edris Valadbeigi
Department of Chemistry, Faculty of Sciences
Islamic Azad University, Karaj Branch, Karaj, Iran
Tel: 00989188313734
Fax: 00988346124463
E-mail: [email protected]

Received date: May 26, 2017; Accepted date: May 27, 2017; Published date: June 03, 2017

Citation: Valadbeigi E, Ghodsi S (2017) Synthesis and Characterization of Some New Thiazolidinedione Derivatives Containing a Coumarin Moiety for their Antibacterial and Antifungal Activities. Med Chem (Los Angeles) 7:178-185. doi:10.4172/2161-0444.1000453

Copyright: © 2017 Valadbeigi E, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Simple coumarins and analogues are large class of compounds that have attracted their interest for a long time due to their biological activities. They have shown to be useful as anti-tumoural, anti-HIV agents and as CNS active compounds. Furthermore, they have been reported to have multiple biological activities (anti-coagulant, anti-inflammatory), although all these properties have not been evaluated systematically. In addition, their enzyme inhibition properties, antimicrobial and antioxidant activities are other foremost topics in this field of research. A new series of thiazolidinedione derivatives were synthesized by reacting with coumarin moiety and studied for their antibacterial and antifungal activities. The synthesis of compounds (6a-9c) was achieved through the versatile and efficient synthetic route that involved reaction of thiazolidinedione with appropriately α-bromo ketone or α-bromo oxime derivatives (2a, 5c). The structures of these compounds were established by means of IR, 1H-NMR, 13C-NMR Mass and elemental analysis.

Keywords

Antimicrobial; Chemical synthesis; Coumarin; Thiazolidinedione

Introduction

The structural and therapeutic diversity of small heterocyclic molecules coupled with their commercial viability has long fascinated organic and medicinal chemists. Heterocycles containing the coumarin ring system include some novel pharmacologically active compounds such as dicumarol, warfarin and novobiocin (Figure 1). Natural coumarins affect the formation and scavenging of ROS and influence free radical-mediated oxidative damage [1]. Azomethine group (-C=N- )-containing compounds, typically known as Schiff ’s bases, have been synthesized via condensation of primary amines with active carbonyls. It is well established that the biological activity of hydrazone compounds is associated with the presence of the active (-CO-NHN=C-) pharmacophore and these compounds form a significant category of compounds in medicinal and pharmaceutical chemistry with several biological applications that include antitumoral [2,3], antifungal [4-9], antibacterial [4-11], antimicrobial [12] and anthelmintic uses [13]. Thiazolidine derivatives are reported to show a variety of biological activities. The presence of a thiazolidine ring in penicillin and related derivatives was the first recognition of its occurrence in nature [14]. Thiazolidine-4-one represents a prevalent scaffold in drug discovery [15]. Literature surveys show that thiazolinylhydrazones exhibit antitubercular and antimicrobial activities [16], and their pronounced antioxidant [17] and antifungal [18] activity has also been reported.

medicinal-chemistry-coumarin-ring-system

Figure 1: Heterocycles containing the coumarin ring system.

The synthesis of coumarins and their derivatives has attracted considerable attention from organic and medicinal chemists for many years as a large number of natural products contain this heterocyclic nucleus. They are widespread in nature as physiologically active constituents of plants [19-21]. In addition, coumarin derivatives have a broad range of applications in the pharmaceutical, perfume, and cosmetic industries. The diverse biological activities of coumarins is well known as anticoagulants, antithrombotics, antimicrobial, antibacterial activities, anticancer and anti-HIV activity [22-28]. Thus, coumarins containing a Schiff ’s base and a thiazolidinone moiety are expected to have enhanced biological activities.

Materials and Methods

Chemistry

Chemical reagents and all solvents used in this research were bought from Merck AG (Darmstadt, Germany). Melting points were determined in open glass capillaries using Bibby Stuart Scientific SMP3 apparatus (Bibby Sterlin Ltd, U.K.) and are uncorrected. The FT-IR spectra were obtained on a Shimadzu 470 spectrophotometer (potassium bromide disks; Shimadzu, Tokyo, Japan). Mass spectra were also recorded with an Agilent Technologies 5973, Mass Selective Detector (MSD) spectrometer (Wilmigton, USA). 1H-NMR spectra were recorded using a Bruker 500 spectrometer and 13C- NMR spectra were recorded using a Bruker 300 spectrometer (Bruker Bioscience, Billerica, MA, USA), and chemical shifts are expressed as δ (ppm) with tetramethylsilane as internal standard. Merck silica gel 60 F254 plates were used for analytical TLC (Merck).'

Experimental

The synthesis of final compounds was obtained via the useful and effective synthetic route indicated in Scheme 1. The starting with 2-hydroxy/ 2-hydroxy-3-methoxy/ 5-boromo-2-hydroxybenzaldehyd and ethylacetoacetate in methanol in the presence of piperidine to give 3-acetyl coumarin, 3-acetyl (5-bromocoumarin) and 3-acetyl (8-methoxy coumarin). Compounds 3-acetyl coumarin, 3-acetyl (5-bromocoumarin) and 3-acetyl (8-methoxy coumarin) were converted to α-bromo intermediate by refluxing with Br2 in CH2Cl2 [29]. α-bromoketones were converted to α-bromo oxioms by stirring with hydroxyl amine hydrochloride, methoxy amine hydrochloride and O-benzyl hydroxylamine hydrochloride in methanol at 22-25°C [29,30]. The final compounds consist of intermediate synthesized reaction with thiazolidinedione in EtOH, in the presence of KOH at 0°C afforded corresponding ketones and oxime derivatives (6a-9c), respectively (Table 1).

medicinal-chemistry-methoxy-amine-hydrochloride

Reagents and conditions: (a) Br2, CH2Cl2, 22-25°C, and then reflux; (b) hydroxylamine hydrochloride, MeOH, 22-25°C; (c) methoxy amine hydrochloride, MeOH, 22-25°C; (d) O-benzyl hydroxylamine hydrochloride, MeOH, 22-25°C; (e), (f), (g), (h) EtOH, KOH, 0°C.
Scheme 1: Synthesis route of compounds 6a-9c.

image
Compound X Y Mp (°C) Reaction time (h) Yield (%) Formula M.W
6a H O 161-163 24 71 C14H9NO5S 303.29
6b 6-Br O 171-173 24 66 C14H8BrNO5S 382.19
6c 8-OMe O 165-167 24 68 C15H11NO6S 333.32
7a H NOH 148-151 24 57 C14H10N2O5S 318.30
7b 6-Br NOH 177-179 24 58 C14H9BrN2O5S 397.20
7c 8-OMe NOH 153-155 24 59 C15H12N2O6S 348.33
8a H NOMe 157-159 24 58 C15H12N2O5S 332.33
8b 6-Br NOMe 178-180 24 60 C15H11BrN2O5S 411.23
8c 8-OMe NOMe 162-164 24 62 C16H14N2O6S 362.06
9a H NOBn 183-185 24 56 C21H16N2O5S 408.43
9b 6-Br NOBn 190-192 24 55 C21H15BrN2O5S 487.32
9c 8-OMe NOBn 186-188 24 54 C22H18N2O6S 438.45

Table 1: Structures and physicochemical data of compounds 6a-9c.

2, 4 thiazolidinedione (C3H3NO2S): In a 250 ml three-necked round-bottomed flask, was placed, solution containing (56.4 g 0.6 mol) of chloracetic acid in 60 ml of water and (45.6 g, 0.6 mol) of thiourea dissolved in 60 ml of water. The mixture was stirred for 15 min. to form a white precipitate, accompanied by considerable cooling. To the contents of the flask was then added slowly 60 ml of concentrated HCl from a dropping funnel, the flask was then connected with a reflux condenser and gentle heat applied to effect complete solution, after which the reaction mixture was stirred and refluxed for 8-10 h at 100- 110°C. On cooling the contents of the flask solidified to a cluster of white needles (Scheme 2). The product was filtered and washed with water to remove traces of hydrochloric acid and dried. It was purified by recrystallization from ethyl alcohol. Yield: (88%); M.p: (122-124)°C.

medicinal-chemistry-thiazolidinedione

Scheme 2: Synthesis of 2, 4-thiazolidinedione.

3-acetyl-2H-chromen-2-one (1a, C11H8O3): (596 mg, 3.8mmol) 2-hydroxybenzaldehyd and ethylacetoacetate (464 mg, 3.8mmol) in (14 ml) methanol in the presence of piperidine was stirred at 0-4°C for 4h. The precipitated yellow solid was filtered off, washed with cold methanol, and dried to give (1a)(869 mg). Yellow solid; M.p:(188-189)°C, yield=(82%); IR (KBr, cm-1): 1734, 1630, 1601, 1572, 1459, 1434, 1363, 1282, 1128, 1094, 1043, 949, 886, 765; 1H-NMR (500 MHz, DMSO-d6): δ=2.44 (s, 3H, CH3coumarin), δ=4.45 (s, 2H,CH2-Br), 7.42 (dt, 1H, H-6 coumarin, J=7.87 and 0.84 Hz), 7.51 (d, 1H, H-8 coumarin, J=6.91 Hz), 7.72 (dt, 1H, H-7coumarin, J=8.64 and 1.53 Hz), 7.92 (dd, 1H, H-5 coumarin, J=7.67 and 1.39 Hz), 8.41 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=32.4, 120.3, 121.8, 127.9, 131.8, 133.2, 136.2, 140.8, 157.5, 164.9, 198.1 ppm; MS (70eV) m/z:[M+], 188 (100%); Anal. Calcd for C11H8O3 188.1794, Found 188.1785.

3-acetyl-6-bromo-2H-chromen-2-one (1b, C11H7BrO3): (585 mg, 2.9mmol) 5-bromo-2-hydroxybenzaldehyd and ethylacetoacetate (378 mg, 2.9mmol) in (14 ml) methanol in the presence of piperidine was stirred at 0-4°C for 4h. The precipitated yellow solid was filtered off, washed with cold methanol, and dried to give (1b) (809 mg). Yellow solid; M.p: (225-227)°C, yield=(84%); IR (KBr, cm-1): 1744, 1633, 1610, 1574, 1455, 1437, 1369, 1288, 1131, 1090, 1049, 941, 888, 671; 1H-NMR (500 MHz, DMSO-d6): δ=2.41 (s, 3H, CH3coumarin), δ=7.20-7.61 (m, 2H, H-7- H-8 coumarin), δ=7.66 (d, 1H, H-5 coumarin, J=8.85), δ=8.52 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=31.9, 120.5, 122.8, 126.6, 134.2, 136.1, 139.8, 141.4, 155.2, 164.5, 197.9 ppm; MS (70eV) m/z: [M+],265 (100%), [M++2], 267(15%), [M+ +4], 269 (2%); Anal. Calcd forC11H7 79BrO3 267.0755, Found 267.0750.

3-acetyl-8-methoxy-2H-chromen-2-one (1c, C12H10O4): (400 mg, 2.6 mmol) 2-hydroxy-3-methoxybenzaldehyd and ethylacetoacetate (335 mg, 2.6 mmol) in (14 ml) methanol in the presence of piperidine was stirred at 0-4°C for 4h. The precipitated yellow solid was filtered off, washed with cold methanol, and dried to give (1c) (605 mg). Yellow solid; M.p:(168-169)°C, yield=(78%); IR(KBr, cm-1): 1738, 1641,1616, 1569, 1466, 1422, 1371, 1277, 1166, 1100, 1044, 943, 890, 766; 1H-NMR (500 MHz, DMSO-d6): δ=2.46 (s, 3H, CH3coumarin), δ=4.04 (s, 3H, O-CH3coumarin), 7.39 (dt, 1H, H-6 coumarin, J=7.85 and 0.81 Hz), 7.79 (dt, 1H, H-7coumarin, J=8.70 and 1.53 Hz), 7.95 (dd, 1H, H-5 coumarin, J=7.68 and 1.40 Hz), 8.48 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=32.1, 57.4, 122.1, 124.2, 127.7, 132.6, 134.6, 140.9, 144.5, 152.4, 164.5, 198.1 ppm; MS (70eV) m/z: [M+],218 (100%); Anal. Calcd for C12H10O4 218.2054, Found 218.2056.

3-(2-bromoacetyl)-2H-chromen-2-one (2a, C11H7BrO3): To a solution of (1a) (500 mg, 2.7mmol) was added Br2 (430 mg, 2.7mmol) in dichloromethane a dropwise. The completion of the reaction was monitored by TLC. The precipitated yellow solid was filtered off, washed with cold methanol, and dried to give (2a) (680 mg). Yellow crystal; M.p: (148-150)°C, yield=(82%); IR (KBr, cm-1): 1733, 1630, 1600, 1562, 1452, 1434, 1366, 1277, 1163, 1094, 1043, 1001, 886, 765; 1H-NMR (500 MHz, DMSO-d6): δ=4.57 (s, 2H,CH2-Br), δ=7.33-7.76 (m, 3H, H-6 and H-7 and H-8 coumarin), δ=7.84 (d, 1H, H-5 coumarin, J=8.70 Hz), δ=8.48 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=35.8, 120.8, 121.9, 128.7, 131.5, 134.8, 136.2, 139.8, 156.2, 166.6, 197.7 ppm; MS (70eV) m/z: [M+],265 (100%), [M++2], 267(20%), [M+ +4], 269 (1.6%); Anal. Calcd for C11H779BrO3 267.0755, Found 267.0752.

6-bromo-3-(2-bromoacetyl)-2H-chromen-2-one (2b, C11H6Br2O3): To a solution of (1b) (500 mg, 1.8mmol) was added Br2 (287 mg, 1.8mmol) in dichloromethane a dropwise. The completion of the reaction was monitored by TLC. The precipitated yellow solid was filtered off, washed with cold methanol, and dried to give (2b) (685 mg). Yellow crystal; M.p: (235-237)°C, yield=(87%);IR (KBr, cm-1): 1731, 1636,1596, 1571, 1449, 1429, 1371, 1276, 1158, 1105, 1050, 1011, 880,669; 1H-NMR (500 MHz, DMSO-d6) : δ=4.47 (s, 2H,CH2-Br), δ=7.42-7.52 (m, 2H, H-7 and H-8 coumarin), δ=7.60 (d, 1H, H-5 coumarin, J=8.81), δ=8.48(s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=35.9, 120.7, 121.6, 126.3, 133.8, 135.7, 136.8, 140.9, 154.8, 164.8, 198.1 ppm; MS (70eV) m/z: [M+],345 (100%), [M++2], 347(25%), [M+ +4], 349 (2%); Anal. Calcd for C11H679Br2O3 345.9715, Found 345.9710.

3-(2-bromoacetyl)-8-methoxy-2H-chromen-2-one (2c, C12H9BrO4): To a solution of (1c) (500 mg, 2.3 mmol) was added Br2 (366 mg, 2.3 mmol) in dichloromethane a dropwise. The completion of the reaction was monitored by TLC. The precipitated yellow solid was filtered off, washed with cold methanol, and dried to give (2c) (702 mg). Yellow crystal; M.p: (178-179)°C, yield=(81%) ; IR (KBr, cm-1): 1720, 1644, 1612, 1555, 1460, 1444, 1370, 1282, 1166, 1099, 1047, 1012, 890, 673; 1H-NMR (500 MHz, DMSO-d6): δ=4.08 (s, 3H, O-CH3coumarin), δ=4.51 (s, 2H,CH2-Br), δ=7.18-7.71 (m, 2H, H-6 and H-7 coumarin), δ=7.75 (d, 1H, H-5 coumarin, J=8.66 Hz), δ=8.47 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=36.5, 57.3, 121.5, 122.7, 128.3, 131.8, 135.1, 142.4, 145.6, 152.5, 162.6, 198.7 ppm; MS (70eV) m/z: [M+],295 (100%), [M++2], 297(30%), [M+ +4], 299 (5%); Anal. Calcd for C12H979BrO4 297.1015, Found 297.1006.

3-(2-bromo-1-(hydroxyimino)ethyl)-2H-chromen-2-one (3a, C11H8BrNO3): A solution of (2a) (267 mg, 1.0 mmol) and hydroxylamine hydrochloride (209 mg, 3.0 mmol) in methanol (10 ml) was stirred at 22-25°C for 24 h. Then, water (25 ml) was added and the precipitate was filtered and washed with water to give compound (3a) (376 mg). White powder; M.p: (185-187)°C, yield=(79%); IR (KBr, cm- 1): 1737, 1674, 1609, 1566, 1449, 1440, 1360, 1280, 1166, 1101, 1046, 1010, 888, 761; 1H-NMR (500 MHz, DMSO-d6): δ=4.42 (s, 2H,CH2- Br), 7.46 (dt, 1H, H-6 coumarin, J=7.87 and 0.84 Hz), 7.51 (d, 1H, H-8 coumarin, J=6.91 Hz), 7.72 (dt, 1H, H-7coumarin, J=8.64 and 1.53 Hz), 7.90 (dd, 1H, H-5 coumarin, J=7.67 and 1.39 Hz), 8.28 (s, 1H, H-4 coumarin), 12.41 (s, 1H,oxime) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=35.7, 120.9, 123.3, 127.6, 130.2, 134.8, 136.4, 140.9, 155.5, 163.8, 198.3 ppm; MS (70eV) m/z: [M+], 280 (100%), [M++2], 282(35%), [M+ +4], 284 (10%); Anal. Calcd for C11H879BrNO3 282.0901, Found 282.0905.

6-bromo-3-(2-bromo-1-(hydroxyimino)ethyl)-2H-chromen-2- one (3b, C11H7Br2NO3): A solution of (2b) (346 mg, 1.0 mmol) and hydroxylamine hydrochloride (209 mg, 3.0 mmol) in methanol (10 ml) was stirred at 22-25°C for 24 h. Then, water (25 ml) was added and the precipitate was filtered and washed with water to give compound (3b) (259 mg). White powder; M.p: (173-175)°C, yield=(75%); IR (KBr, cm- 1): 1728, 1635, 1609, 1560, 1459, 1430, 1360, 1279, 1174, 1092, 1048, 994, 892, 670; 1H-NMR (500 MHz, DMSO-d6): δ=4.22 (s, 2H,CH2- Br), δ=7.20 -7.57 (m, 2H, H-7 and H-8 coumarin), δ=7.64 (d, 1H, H-5 coumarin,J=8.78), δ=8.22 (s, 1H, H-4 coumarin), δ=12.48(s, 1H, oxime) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=36.8, 121.1, 123.9, 126.4, 134.5, 136.2, 137.7, 139.8, 155.6, 164.6, 198.9 ppm; MS (70eV) m/z: [M+], 360 (100%), [M++2], 362(15%), [M+ +4], 364 (2%); Anal. Calcd for C11H779Br2NO3 360.9862, Found 360.9855.

3-(2-bromo-1-(hydroxyimino)ethyl)-8-methoxy-2H-chromen- 2-one (3c, C12H10BrNO4): A solution of (2c) (297 mg, 1.0 mmol) and hydroxylamine hydrochloride (209 mg, 3.0 mmol) in methanol (10 ml) was stirred at 22-25°C for 24 h. Then, water (25 ml) was added and the precipitate was filtered and washed with water to give compound (3c) (389 mg). White powder; M.p: (165-167)°C, yield=(77%); IR (KBr, cm-1): 1730,1723, 1677, 1615, 1444, 1361, 1258, 1171, 1025, 955, 835, 760; 1H-NMR (500 MHz, DMSOd6): δ=4.06 (s, 3H,O-CH3coumarin), δ=4.41 (s, 2H, CH2-Br), 7.51 (dt, 1H, H-6 coumarin, J=7.91 and 0.88 Hz), 7.72 (dt, 1H, H-7coumarin, J=8.68 and 1.56 Hz), 7.93 (dd, 1H, H-5 coumarin, J=7.71 and 1.38 Hz), 8.33 (s, 1H, H-4 coumarin), 12.39 (s, 1H,oxime) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=36.1, 57.6, 121.1, 123.9, 126.4, 130.5, 134.7, 141.1, 145.5, 152.6, 163.6, 197.8 ppm; MS (70eV) m/z: [M+], 310 (100%), [M++2], 312(20%), [M+ +4], 314 (1.6%); Anal. Calcd for C12H10 79BrNO4 312.1161, Found 312.1164.

3-(2-bromo-1-(methoxyimino)ethyl)-2H-chromen-2-one (4a, C12H10BrNO3): To a stirred solution of (2a) (267 mg, 1.0 mmol) in MeOH (16 ml) at 22-25°C, was added 25% solution of O-methyl hydroxyl ammonium chloride in diluted HCl (1002 mg, 3.0 mmol). After 24 h stirring at 22-25°C, the precipitated white solid was filtered off, washed with cold methanol, and dried to give (4a) (977 mg). White powder; M.p: (151-153)°C, yield=(77%); IR (KBr, cm-1): 1729, 1669, 1611, 1558, 1455, 1429, 1365, 1284, 1111, 1099, 1041, 995, 894, 769; 1H-NMR (500 MHz, DMSO-d6): δ4.12 (s, 3H, O-CH3oxime), 4.51 (s, 2H,CH2-Br), 7.38 (t, 1H, H-6 coumarin, J=7.39 Hz), 7.48 (d, 1H, H-8coumarin, J=8.67 Hz), 7.62-7.89 (m, 2H, H-5 and H-7 coumarin), 8.15(s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=35.4, 64.8, 120.6, 123.8, 128.3, 131.9, 134.2, 136.1, 143.1, 157.1, 165.4, 198.1 ppm; MS (70eV) m/z: [M+],294 (100%), [M++2], 296(35%), [M+ +4], 298 (10%); Anal. Calcd for C12H1079BrNO3 296.1167, Found 296.1163.

6-bromo-3-(2-bromo-1-(methoxyimino)ethyl)-2H-chromen- 2-one (4b, C12H9Br2NO3): To a stirred solution of (2b) (346 mg, 1.0 mmol) in MeOH (16 ml) at 22-25°C, was added 25% solution of O-methyl hydroxyl ammonium chloride in diluted HCl (1002 mg, 3.0 mmol). After 24 h stirring at 22-25°C, the precipitated white solid was filtered off, washed with cold methanol, and dried to give (4b) (996 mg). M.p: (158-160)°C, yield=(74%); IR (KBr, cm-1): 1731, 1641, 1612, 1570, 1447, 1439, 1364, 1276, 1156, 1088, 1056, 1014, 896, 663; 1H-NMR (500 MHz, DMSO-d6): δ=4.11 (s, 3H, O-CH3oxime), δ=4.24 (s, 2H,CH2- Br), δ=7.01-7.50 (m, 2H, H-7 and H-8 coumarin), δ=8.33 (d, 1H, H-5 coumarin,J=8.75), δ=8.29 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=36.4, 64.8, 119.9 122.6, 127.6, 130.6, 132.6, 136.1, 139.8, 156.8, 163.8, 198.3 ppm; MS (70eV) m/z: [M+], 374 (100%), [M++2], 376(18%), [M+ +4], 378 (2.5%); Anal. Calcd for C12H979Br2NO3 375.0128, Found 375.0118.

3-(2-bromo-1-(methoxyimino)ethyl)-8-methoxy-2H-chromen- 2-one (4c, C13H12BrNO4): To a stirred solution of (2c) (297 mg, 1.0 mmol) in MeOH (16 ml) at 22-25°C, was added 25% solution of O-methyl hydroxyl ammonium chloride in diluted HCl (1002 mg, 3.0 mmol). After 24 h stirring at 22-25°C, the precipitated white solid was filtered off, washed with cold methanol, and dried to give (4c)(987 mg). White powder; M.p: (141-143)°C, yield=(76%); IR (KBr, cm-1): 1726, 1636, 1601, 1576, 1461, 1429, 1368, 1251, 1123, 1097, 1053, 1014, 891, 761; 1H-NMR (500 MHz, DMSO-d6): δ=4.06(s, 3H, O-CH3coumarin), δ=4.25 (s, 2H,CH2-Br), δ=4.15 (s, 3H, O-CH3oxime), 7.41 (t, 1H, H-6 coumarin, J=7.42 Hz), 7.62-7.89 (m, 2H, H-5 and H-7 coumarin), 8.18(s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=36.3, 57.4, 65.5, 121.8, 122.7, 127.8, 131.7, 134.9, 141.7, 144.8, 152.4, 164.8, 198.1 ppm; MS (70eV) m/z: [M+], 324 (100%), [M++2], 326(25%), [M+ +4], 328 (2%); Anal. Calcd for C13H1279BrNO4 326.1427, Found 326.1421.

3-(2-bromo-1-(methoxyimino)ethyl)-8-methoxy-2H-chromen- 2-one (4c, C13H12BrNO4): To a stirred solution of (2c) (297 mg, 1.0 mmol) in MeOH (16 ml) at 22-25°C, was added 25% solution of O-methyl hydroxyl ammonium chloride in diluted HCl (1002 mg, 3.0 mmol). After 24 h stirring at 22-25°C, the precipitated white solid was filtered off, washed with cold methanol, and dried to give (4c)(987 mg). White powder; M.p: (141-143)°C, yield=(76%); IR (KBr, cm-1): 1726, 1636, 1601, 1576, 1461, 1429, 1368, 1251, 1123, 1097, 1053, 1014, 891, 761; 1H-NMR (500 MHz, DMSO-d6): δ=4.06(s, 3H, O-CH3coumarin), δ=4.25 (s, 2H,CH2-Br), δ=4.15 (s, 3H, O-CH3oxime), 7.41 (t, 1H, H-6 coumarin, J=7.42 Hz), 7.62-7.89 (m, 2H, H-5 and H-7 coumarin), 8.18(s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=36.3, 57.4, 65.5, 121.8, 122.7, 127.8, 131.7, 134.9, 141.7, 144.8, 152.4, 164.8, 198.1 ppm; MS (70eV) m/z: [M+], 324 (100%), [M++2], 326(25%), [M+ +4], 328 (2%); Anal. Calcd for C13H12 79BrNO4 326.1427, Found 326.1421.

3-(1-(benzyloxyimino)-2-bromoethyl)-6-bromo-2H-chromen- 2-one (5b, C18H13Br2NO3): A solution of (2b) (346 g, 1.0 mmol) and O-benzyl hydroxyl amine hydrochloride (0.479 g, 3.0 mmol) in methanol (16 ml) was stirred at 22-25°C overnight. The resulting suspension was cooled 0-4°C and the precipitated white solid was filtered off, washed with cold methanol, and dried to give 544 mg (5b). White powder; M.p: (105-107)°C, yield=(66%); IR (KBr,cm-1): 1719, 1625, 1616, 1456, 1369, 1245, 1171, 1105, 1049, 888, 776, 733; 1H-NMR (500 MHz, DMSO-d6): δ=4.51 (s, 2H, CH2-Br), δ=5.39 (s, 2H, O-CH2- Ph), δ=7.35 -7.57 (m, 7H, H7,H8coumarin and phenyl), δ=7.71 (d, 1H, H5coumarin, J=8.71), δ=8.11 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=36.9, 79.1, 122.2, 128.4, 129.7(2C), 130.8, 132.3(2C), 134.2, 135.8, 137.2, 141.5, 146.3, 153.8, 165.1, 171.9, 183.8 ppm; MS (70eV) m/z: [M+], 450 (100%), [M++2], 452(15%), [M+ +4], 454 (2%); Anal. Calcd for C18H13 79Br2NO3 451.1087, Found 451.1081.

3-(1-(benzyloxyimino)-2-bromoethyl)-8-methoxy-2Hchromen- 2-one (5c, C19H16BrNO4): A solution of (2c) (297mg, 1.0 mmol) and O-benzyl hydroxyl amine hydrochloride (0.479 g, 3.0 mmol) in methanol (16 ml) was stirred at 22-25°C overnight. The resulting suspension was cooled 0-4°C and the precipitated white solid was filtered off, washed with cold methanol, and dried to give 527 mg (5c). White powder; M.p: (105-107)°C, yield=(68%); IR (KBr,cm-1): 1715, 1621, 1607, 1450, 1362, 1239, 1165, 1094, 1051, 881, 765, 7341H-NMR(500 MHz, DMSO-d6): δ=3.76 (s, 3H, O-CH3coumarin), δ=4.44 (s, 2H, CH2-Br), δ=5.36 (s, 2H, O-CH2-Ph), δ=7.35 -7.55 (m, 7H, H-6,H7, coumarin and phenyl), δ=7.81 (d, 1H, H5-coumarin. J=7.72), δ=8.00 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=37.2, 57.8, 79.9 122.5, 125.7, 127.6, 128.7(2C), 130.9, 133.5(2C), 134.8, 136.4, 138.9, 145.1, 153.2, 163.4, 172.8, 183.1 ppm; MS (70eV) m/z: [M+], 401 (100%), [M++2], 403(18%), [M+ +4], 405 (2.5%); Anal. Calcd for C19H16 79BrNO4 402.2386, Found 402.2379.

General procedure for the synthesis of compounds 6a-9c

A mixture of (2a-c) or oxime derivatives (3a-5c) (0.5 mmol), thiazolidinedione (0.5 mmol), and KOH (0.5 mmol) in EtOH (10ml), was stirred at 0°C for 24h. After consumption of thiazolidinedione, water (20 ml) was added and the precipitate was filtered, washed with water, and recrystallized from methanol-chloroform (9:1) to give compounds (6a-9c).

3-(2-oxo-2-(2-oxo-2H-chromen-3-yl)ethyl)thiazolidine- 2,4-dione(6a, C14H9NO5S): Brown powder; M.p: (161-163)°C, yield=(71%); IR (KBr, cm-1) : 1758, 1609, 1589, 1494, 1459, 1375, 1282, 1279 1104, 756; 1H-NMR (500 MHz, DMSO-d6): δ=4.17(s, 2H, CH2-thiazolidinedione), δ=5.26 (s, 2H,COCH2), δ=7.44 (t, 1H, H-6 coumarin, J=7.76 Hz), δ=7.49 (d, 1H, H-8 coumarin, J=8.35 Hz), δ=7.77 (dt, 1H, H-7 coumarin, J=7.79 and1.46 Hz), δ=7.97 (dd, 1H, H-5 coumarin, J=6.59 and 1.36 Hz), δ=8.57 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=40.9, 60.4, 120.5, 122.8, 128.6, 131.2, 132.8, 135.6, 140.4, 156.4, 164.6, 171.1, 174.6, 198.7 ppm; MS (70eV) m/z: [M+], 303 (100%); Anal. Calcd for C14H9NO5S 303.2900, Found 303.2894.

3-(2-(6-bromo-2-oxo-2H-chromen-3-yl)-2-oxoethyl) thiazolidine-2,4-dione(6b, C14H8BrNO5S): Brown powder; M.p: (171- 173)°C, yield=(66%); IR (KBr, cm-1) : 1760, 1608, 1580, 1490, 1455, 1379, 1291, 1284, 1119, 759; 1H-NMR (500 MHz, DMSO-d6) : δ=4.18 (s, 2H, CH2-thiazolidinedione), δ=5.22 (s, 2H, COCH2), δ=7.29-7.52 (m, 2H, H-7,8 coumarin), δ=7.65 (d, 1H, H-5 coumarinJ=8.80Hz), δ=8.49 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=40.1, 60.3, 119.8, 122.6, 127.3, 133.8, 135.6, 136.8, 140.3, 155.8, 163.8, 169.5, 174.1, 198.6 ppm; MS (70eV) m/z: [M+], 382 (100%), [M++2], 384(18%), [M+ +4], 386 (2.5%); Anal. Calcd for C14H8 79BrNO5S 382.1860, Found 382.1852.

3-(2-(8-methoxy-2-oxo-2H-chromen-3-yl)-2-oxoethyl) thiazolidine-2,4-dione(6c, C15H11NO6S): Brown powder; M.p: (165- 167)°C, yield=(68%); IR (KBr, cm-1) : 1756, 1611, 1594, 1501, 1463, 1369, 1287, 1271, 1111, 767; 1H-NMR (500 MHz, DMSO-d6) : δ=4.09 (s, 3H, O-CH3 coumarin), δ=4.17 (s, 2H, CH2-thiazolidinedione), δ=5.27(s, 2H, COCH2), δ=7.27-7.44 (m, 2H, H-6, H-7 coumarin), δ=7.90 (d, 1H, H-5 coumarin, J=8.71 Hz), 8.44 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=39.8, 58.6, 61.3, 121.6, 123.7, 127.3, 131.2, 135.6, 140.4, 144.4, 151.3, 163.7, 172.8, 175.1, 198.6 ppm; MS (70eV) m/z: [M+], 333 (100%); Anal. Calcd for C15H11NO6S 333.3159, Found 333.3154.

3-(2-(hydroxyimino)-2-(2-oxo-2H-chromen-3-yl)ethyl) thiazolidine-2,4-dione(7a, C14H10N2O5S): Brown powder; M.p: (148-151)°C, yield=(57%); IR (KBr,cm-1): 3428, 2926, 1755, 1611, 1587, 1493, 1464, 1377, 1280, 1279, 1106, 761; 1H-NMR (500 MHz, DMSO-d6) : δ=4.21(s, 2H, CH2-thiazolidinedione), δ=4.95 (s, 2H, CNOH-CH2), δ=7.40 (t, 1H, H-6 coumarin, J=7.62 Hz), δ=7.56 (d, 1H, H-8 coumarin, J=7.34 Hz), δ=7.66 (dt, 1H, H-7 coumarin, J=7.33 and 1.26 Hz), δ=7.77 (d, 1H, H-5 coumarin, J=7.69 Hz), δ=8.14 (s, 1H, H-4 coumarin),δ=11.26(s, 1H, oxime) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=40.3, 57.3, 121.6, 122.3, 127.9, 130.8, 132.2, 133.8, 141.6, 155.9, 163.4, 171.9, 173.8, 186.6 ppm; MS (70eV) m/z: [M+], 318 (100%); Anal. Calcd for C14H10N2O5S 318.0310, Found 318.0304.

3-(2-(6-bromo-2-oxo-2H-chromen-3-yl)-2-(hydroxyimino) ethyl)thiazolidine-2,4-dione (7b, C14H9BrN2O5S): Brown powder; M.p: (177-179)°C, yield=(58%); IR (KBr, cm-1) : 3352, 2929, 1760, 1609, 1592, 1491, 1455, 1371, 1294, 1205, 1118, 767; 1H-NMR (500 MHz, DMSO-d6) : δ=4.15 (s, 2H, CH2-thiazolidinedione), δ=4.93(s, 2H, CNOH-CH2), δ=7.27-7.43 (m,2H, H-7 and H-8 coumarin), δ=7.68 (d, 1H, H-5 coumarin, J=8.74Hz), δ=8.07 (s, 1H, H-4 coumarin), δ=11.28 (s, 1H, oxime) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=40.3, 55.2, 120.3, 122.8, 126.8, 133.4, 134.7, 136.5, 140.8, 154.1, 164.2, 168.3, 173.5, 185.9 ppm; MS (70eV) m/z: [M+], 397 (100%), [M++2], 399(18%), [M+ +4], 401 (2.5%); Anal. Calcd for C14H9 79BrN2O5S 397.2007, Found 397.2001.

3-(2-(hydroxyimino)-2-(8-methoxy-2-oxo-2H-chromen-3-yl) ethyl)thiazolidine-2,4-dione(7c, C15H12N2O6S): Brown powder; M.p:(153-155)°C, yield=(59%); IR (KBr, cm-1) : 3435, 2932, 1750, 1620, 1595, 1488, 1462, 1383, 1288, 1209, 1100, 781; 1H-NMR (500 MHz, DMSO-d6) : δ=4.19 (s, 2H, CH2-thiazolidinedione), δ=4.05(s, 3H, O-CH3 coumarin), δ=4.90 (s, 2H, CNOH-CH2), δ=7.48 (dt, 1H, H-6 coumarin, J=7.84 and 0.81 Hz), δ=7.75 (dt, 1H, H-7coumarin, J=8.71 and 1.58 Hz), δ=7.91 (dd, 1H, H-5 coumarin, J=7.69 and1.36 Hz), δ=8.25(s, 1H, H-4 coumarin), δ=11.32 (s, 1H, oxime) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=39.5, 54.1, 58.8, 121.6, 124.6, 127.9, 132.6, 136.3, 139.4, 143.6, 152.6, 164.2, 171.8, 174.3, 185.1 ppm;MS (70eV) m/z: [M+], 348 (100%); Anal. Calcd for C15H12N2O6S 348.3306, Found 348.3312.

3-(2-(methoxyimino)-2-(2-oxo-2H-chromen-3-yl)ethyl) thiazolidine-2,4-dione(8a, C15H12N2O5S): Brown powder; M.p:(157- 159)°C, yield=(58%); IR (KBr, cm-1) : 3425, 2934, 1757, 1615, 1595, 1488, 1468, 1382, 1278, 1221, 1114, 763; 1H-NMR (500 MHz, DMSO-d6): δ=4.08 (s, 3H, O-CH3 oxime), δ=4.17 (s, 2H, CH2-thiazolidinedione), δ=4.87(s, 2H,C-CH2-N), δ=7.34 (t, 1H, H-6 coumarin, J=7.52 Hz), δ=7.39 (d, 1H, H-8 coumarin, J=8.62 Hz), δ=7.56-7.62 (m, 2H, H-5 and H-7coumarin), 8.16 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=39.8, 57.1, 63.9, 120.9, 123.4, 126.5, 130.1, 133.6, 134.2, 142.3, 154.8, 164.2, 172.1, 173.6, 185.3 ppm; MS (70eV) m/z: [M+], 332 (100%); Anal. Calcd for C15H12N2O5S 332.3312, Found 332.3303.

3-(2-(6-bromo-2-oxo-2H-chromen-3-yl)-2-(methoxyimino) ethyl)thiazolidine-2,4-dione (8b, C15H11BrN2O5S): Brown powder; M.p: (178-180)°C, yield=(60%); IR (KBr, cm-1) : 3345, 2923, 1751, 1616, 1592, 1495, 1462, 1379, 1288, 1265, 1110, 755; 1H-NMR (500 MHz, DMSO-d6): δ=4.09 (s, 3H, O-CH3 oxime), δ=4.20 (s, 2H,CH2- thiazolidinedione), δ=4.88 (s, 2H, C-CH2-N), δ=7.01-7.55 (m, 2H, H-7, H-8 coumarin), δ=7.75 (d,1H, H-5 coumarin, J=8.76Hz) δ=8.07 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=41.4, 57.6, 64.3, 120.9, 123.2, 127.1, 133.4, 134.7, 135.9, 141.2, 155.6, 163.6, 167.6, 172.9, 184.6 ppm; MS (70eV) m/z: [M+], 409 (100%), [M++2], 411(18%), [M+ +4], 413 (2.5%); Anal. Calcd for C15H11 79BrN2O5S 411.2272, Found 411.2265.

3-(2-(8-methoxy-2-oxo-2H-chromen-3-yl)-2-(methoxyimino) ethyl)thiazolidine-2,4-dione(8c, C16H14N2O6S): Brown powder; M.p: (162-164)°C, yield=(62%); IR (KBr, cm-1) : 3321, 2933, 1758, 1614, 1586, 1489, 1452, 1380, 1289, 1206, 1099, 758; 1H-NMR (500 MHz, DMSO-d6): δ=4.03 (s, 3H, O-CH3 coumarin),δ=4.12 (s, 3H, O-CH3 oxime), δ=4.21 (s, 2H, CH2-thiazolidinedione), δ=4.92 (s, 2H, 2H, C-CH2-N), δ=7.45 (t, 1H, H-6 coumarin, J=7.45 Hz), δ=7.52-7.66 (m, 2H, H-5, H-7 coumarin), δ=8.05 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=39.9, 55.6, 57.9, 64.1, 122.9, 125.1, 128.3, 133.1, 136.6, 138.3, 145.9, 151.8, 163.8, 169.6, 171.9, 184.3 ppm; MS (70eV) m/z: [M+], 362 (100%); Anal. Calcd for C16H14N2O6S 362.3572, Found 362.3563.

3-(2-(benzyloxyimino)-2-(2-oxo-2H-chromen-3-yl)ethyl) thiazolidine-2,4-dione(9a, C21H16N2O5S): Brown powder; M.p: (183- 185)°C, yield=(56%); IR (KBr, cm-1) : 3425, 2920, 1759, 1619, 1586, 1502, 1455, 1384, 1279, 1204, 1108, 1030, 761; 1H-NMR (500 MHz, DMSO-d6) : δ=3.99 (s, 2H, CH2-thiazolidinedione), δ=4.87(s, 2H, C-CH2-N), δ=5.30 (s, 2H, O-CH2-Ph), δ=7.33-7.57 (m, 7H, H-6, H-8 coumarin and phenyl), 7.61-7.77 (m, 2H, H-5 and H-7 coumarin), δ=8.05 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=40.1, 56.9, 80.8, 122.9, 123.4, 125.7, 127.8, 129.1(2C), 130.8, 131.2 (2C), 132.8, 134.5, 139.6, 142.3, 154.8, 162.9, 171.1, 173.6, 184.8 ppm; MS (70eV) m/z: [M+], 408 (100%); Anal. Calcd for C21H16N2O5S 408.4271, Found 408.4265.

3-(2-(benzyloxyimino)-2-(6-bromo-2-oxo-2H-chromen-3yl) ethyl)thiazolidine-2,4-dione (9b, C21H15BrN2O5S): Brown powder; M.p: (190-192)°C, yield=(55%); IR (KBr, cm-1) : 3345, 2931, 1751, 1621, 1584, 1498, 1460, 1381, 1279, 1206, 1096, 1036, 751; 1H-NMR (500 MHz, DMSO-d6) : δ=4.18 (s, 2H, CH2-thiazolidinedione) δ=5.39 (s, 2H, O-CH2-Ph), δ=4.88 (s, 2H, C-CH2-N), δ=5.24 (s, 2H, O-CH2-Ph), δ=7.01-7.55 (m, 7H,H-7,H-8 coumarin and phenyl), δ=7.72 (d,1H,H-5 coumarin, J=8.82Hz), δ=8.07 (s,1H,H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=40.1, 56.8, 63.3, 79.8, 121.6, 123.2, 127.1, 129.6 (2C), 130.1, 131.9 (2C), 133.1, 135.1, 136.3, 140.9, 154.9, 164.2, 166.8, 171.3, 183.7 ppm; MS (70eV) m/z: [M+], 485 (100%), [M++2], 487(18%), [M+ +4], 489 (2.5%); Anal. Calcd for C21H15 79BrN2O5S 487.3232, Found 487.3224.

3-(2-(benzyloxyimino)-2-(8-methoxy-2-oxo-2H-chromen3yl) ethyl)thiazolidine-2,4-dione(9c, C22H18N2O6S): Brown powder; M.p: (186-188)°C, yield=(54%); IR (KBr, cm-1) : 3311, 2922, 1754, 1600, 1591, 1492, 1467, 1369, 1286, 1216, 1116, 1026, 758; 1H-NMR (500 MHz, DMSO-d6): δ=4.02 (s, 3H, O-CH3 coumarin), δ=4.21 (s, 2H, CH2-thiazolidinedione), δ=4.92 (s, 2H, C-CH2-N), δ=5.27 (s, 2H, O-CH2-Ph), δ=7.31-7.66 (m, 7H, H-6, H-7 coumarin and phenyl), δ=7.84 (d, 1H, H5-coumarin, J=7.74Hz), δ=8.05 (s, 1H, H-4 coumarin) ppm; 13C-NMR (300 MHz, DMSO-d6): δ=40.3, 54.2, 57.3, 63.8, 79.6, 122.1, 124.8, 127.3, 128.9 (2C), 130.6, 132.1 (2C), 134.6, 135.8, 138.6, 143.8, 152.4, 164.1, 168.9, 172.1, 183.5 ppm; MS (70eV) m/z: [M+], 438 (100%); Anal. Calcd for C22H18N2O6S 438.4531, Found 438.4523.

Antimicrobial and antifungal assay

The antimicrobial activity was assayed by cup-plate agar diffusion method [31,32] by measuring inhibition zones in mm. In vitro antimicrobial activity of all synthesized compounds and standard drugs have been evaluated against two strains of bacteria which include grampositive bacteria such as, Bacillus subtilis PTCC 1207 and gram-negative bacteria such as Escherichia coli PTCC 1047 and fungus Candida kefyr ATCC 38296. The antibacterial and antifungal activity was compared with standard drugs. The purified products were screened for their antibacterial activity by using cup-plate agar diffusion method. The nutrient agar broth prepared by the usual method, was inoculated aseptically with 0.5 ml of 24 h old subculture of, Bacillus subtilis PTCC 1047, and Escherichia coli PTCC 1047 in separate conical flasks at 40- 50°C and mixed well by gently shaking. About 25 ml of the contents of the flask was poured and evenly spread in a petri dish (90 mm in diameter) and allowed to set for 2 h. The cups (10 mm in diameter) were formed by the help of borer in agar medium and filled with 0.4 ml (400 μg / ml) solution of sample in DMSO.

The plates were incubated at 37°C for 24 h and the control was also maintained with 0.4 ml of DMSO in a similar manner and the zones of inhibition of the bacterial growth were measured in millimeter and recorded in Table 2 and Figure 2. Candida kefyr ATCC 38296 was employed for testing antifungal activity by cup-plate agar diffusion method. The culture was maintained on Sub rouse dextrose agar slants. Sterilized Sub rouse dextrose agar medium was inoculated with 72 h old 0.5 ml suspension of fungal spores in a separate flask. About 25 ml of the inoculated medium was evenly spread on a sterilized petri dish and allowed to set for 2 h. The cups (10 mm in diameter) were punched in a petri dish and loaded with 0.4 ml (400 μg/ ml) of solution of sample in DMSO. The plates were incubated at 30°C for 48 h. After the completion of incubation period, the zones of inhibition of growth in the form of diameter in mm were measured. Along with the test solution in each petri dish one cup was filled up with solvent which acts as a control. The zones of inhibition are recorded in Table 2 and Figure 2.

image

Compound X Y Diameter of the zone of the inhibition (mm)
Gram-positive organism Gram-negative organism Fungus
Bacillus subtilis
PTCC 1207
Escherichia coli
PTCC 1047
Candida kefyr
ATCC 38296
6a H O 15 16 7
6b 6-Br O 17 17 8
6c 8- OCH3 O 16 19 7
7a H NOH 19 20 9
7b 6-Br NOH 17 16 8
7c 8- OCH3 NOH 20 15 8
8a H NOCH3 25 21 9
8b 6-Br NOCH3 24 20 9
8c 8- OCH3 NOCH3 26 22 8
9a H NOBn 22 19 9
9b 6-Br NOBn 23 21 8
9c 8- OCH3 NOBn 21 19 8
Ciprofloxacin - 23 26  
Ampicillin - 15 18 -
Gentamicin - 21 19 -
Nistatin - - - 12

Table 2: In vitro antibacterial and antifungal activities of compounds 6a-9c.

medicinal-chemistry-coumarin-ring-system

Figure 2: In-vitro antibacterial and antifungal activities of compounds 6a-9c.

Results and Discussion

In this study the structure of the synthesized compounds was elucidated by means of IR, 1H-NMR, 13C-NMR and Mass. All the compounds were evaluated for antibacterial and antifungal activities by cup-plate method. The antimicrobial activity of tested compounds against different strains of bacteria and fungus is shown in Table 2 and Figure 2. The newly synthesized compounds 6a–9c were evaluated for their in-vitro antibacterial activity against Bacillus subtilis PTCC 1207, Escherichia coli PTCC 1047 and Candida kefyr ATCC 38296 using conventional by cup-plate agar diffusion method [31,32]. The zone of growth inhibition values were determined by comparison to standard drugs. The zones of growth inhibition obtained for compounds 6a–9c are presented in Table 2 and Figure 2. The zone of growth inhibition values of the test derivatives indicated that most compounds exhibit good activity against gram-positive and gram-negative bacteria. Antibacterial screening of compounds 6a–9c against gram-positive and gram-negative bacteria reveals that compounds 8a, 8b and 8c exhibit the most potent in-vitro antibacterial activity. All compounds show improvement of activity against gram-negative bacteria in comparison to standard drugs. Generally, in both gram-positive and gram-negative bacteria, better results are obtained with 2-NOCH3 on the ethyl spacer of coumarin. In conclusion, some of the new thiazolidinedione derivatives 6a-9c containing a carbonyl related functional groups (ketone, oxime, O-methyloxime, and O-benzyloxime) on the ethyl spacer showed considerable antibacterial activity and ethyl spacer functionality produced relatively major changes in terms of activity. In general, the results of antibacterial evaluation of the test compounds in comparison with the reference drugs indicated that compounds 8a, 8b and 8c showed comparable or more potent antibacterial activity with respect to the reference drugs against all tested species. The antifungal data reveals that all compounds have shown weak antifungal activity as compared to Nistatin.

Acknowledgements

The authors of the present paper acknowledge Tabriz University for the helpful support of the work.

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