Abstract
The title compounds 6a–j, 2-[(6-methyl-1,3-benzothiazol-2-yl)amino]-N-[2-(substituted phenyl/furan-2-yl)-4-oxo-1,3-thiazolidin-3-yl]nicotinamides, were prepared from 2-chloropyridine-3-carboxylic acid (1) and 2-amino-6-methyl-benzothiazole (2) by known methods. All the compounds have been established by IR, 1H NMR, 13C NMR and elemental analyses. The in vitro antimicrobial screening of the compounds were carried out against two Gram positive (S. aureus, S. pyogenes), two Gram negative (E. coli, P. aeruginosa) bacteria and three fungal species (C. albicans, A. niger, A. clavatus) using the broth microdilution method. Some of the compounds are comparable with standard drugs.
Keywords: Antimicrobial activity, Schiff bases, 4-Thiazolidinones, Nicotinic acid
Introduction
A large number of drugs and biologically relevant molecules contain heterocyclic systems. Often the presence of hetero atoms or groupings imparts preferential specificities in their biological responses. The chemistry and biological study of heterocyclic compounds has been interesting field for a long time due to medicinal and agricultural reasons. The number of heterocyclic derivatives containing nitrogen and sulfur atom possess broad spectrum of biological activities. One of the most important heterocycle in medicinal chemistry is pyridine with wide application including antimicrobial, anti-inflammatory, anti-HIV, antiplasmodial, anti-tubercular, antibacterial and anticonvulsant [1–7] activities, and has much other important biological significance.
The 4-thiazolidinone ring system comprises the broad spectrum for a number of biologically active compounds. In recent years, 4-thiazolidinones are the most extensively investigated class of compounds, which exhibit various biological activities, such as antimicrobial, anti-inflammatory, anti-HIV, anti-toxoplasma gondii and analgesic [8–12].
Looking towards literature, it was thought that incorporation of all these biologically active moieties might be result in better antimicrobial activity and therefore as the part of our continuous research in developing the new heterocycles containing nitrogen and sulfur atom and screening their microbial studies [13–15], herewith we have designed 4-thiazolidinones incorporated nicotinic acid with 2-amino-6-methylbenzothiazole and examined their antimicrobial activities.
Results and Discussion
Synthesis of compounds
2-Chloro pyridine-3-carboxylic acid 1 and 2-amino-6-methyl benzothiazole 2 in presence of anhydrous K2CO3 and Cu-bronze in DMF solvent on Ullmann condensation yielded 2-[(6-methyl-2-benzothiazolyl)amino]nicotinic acid (3). Further heating 3 with SOCl2 and subsequent reaction with hydrazine hydrate in chloroform formed 4 which on condensation with substituted aromatic aldehydes in DMF gave 5a–j. Thaizolidinones 6a–j were synthesized by refluxing 5a–j and thioglycolic acid in dry 1,4-dioxane for 12–14 h using a Dean-Stark apparatus (Scheme 1). Purity of the compounds was checked by TLC using ethyl acetate: toluene (1:3) as a solvent system. Structures were characterized by spectral data (FT-IR, 1H-NMR and 13C-NMR).
Sch. 1.
Reagents and conditions: (a) Ullmann condensation, Cu-Bronze, anhydrous K2CO3, DMF, reflux 5 h; (b) (i) SOCl2 and (ii) NH2NH2·H2O in CHCl3; (c) substituted aromatic aldehydes, DMF, reflux 5–6 h; (d) HSCH2COOH, anhydrous ZnCl2, 1,4-dioxane 12–14 h.
Investigations, Results and Discussion
The in vitro antibacterial and antifungal activities of the compounds are shown in Table 1. The MICs (μg/ml) were carried out by broth microdilution method as described by Rattan [17].
Tab. 1.
Antibacterial and antifungal activities of 5a–j and 6a–j
| Comp. | Minimal bactericidal concentration μg/ml | Minimal fungicidal concentration μg/ml | |||||
|---|---|---|---|---|---|---|---|
| Gram negative | Gram positive | ||||||
| E. coli | P. aerug. | S. aureus | S. pyogenus | C. albicans | A. niger | A. clavatus | |
| 1 | 150 | 150 | 200 | 250 | 250 | 500 | 500 |
| 2 | 250 | 125 | 500 | 1000 | 1000 | 1000 | 1000 |
| 3 | 500 | 1000 | 500 | 1000 | 500 | 250 | 250 |
| 4 | 500 | 500 | 150 | 200 | 250 | 1000 | 1000 |
| 5a | 100 | 500 | 150 | 200 | 100 | 500 | 500 |
| 5b | 500 | 500 | 500 | 100 | 1000 | 1000 | >1000 |
| 5c | 500 | 500 | 1000 | 1000 | 1000 | >1000 | >1000 |
| 5d | 250 | 62.5 | 500 | 500 | 250 | 1000 | 1000 |
| 5e | 62.5 | 150 | 100 | 200 | 1000 | 500 | 500 |
| 5f | 200 | 250 | 150 | 250 | 1000 | 1000 | 1000 |
| 5g | 250 | 500 | 500 | 1000 | 150 | 500 | 500 |
| 5h | 200 | 200 | 62.5 | 62.5 | >1000 | >1000 | >1000 |
| 5i | 500 | 500 | 500 | 500 | >1000 | 500 | >1000 |
| 5j | 25 | 50 | 50 | 62.5 | 100 | 500 | 500 |
| 6a | 250 | 250 | 500 | 500 | 1000 | 1000 | 1000 |
| 6b | 500 | 500 | 150 | 500 | 150 | 1000 | 1000 |
| 6c | 500 | 1000 | 1000 | 100 | >1000 | >1000 | >1000 |
| 6d | 50 | 100 | 100 | 150 | >1000 | 1000 | 500 |
| 6e | 250 | 250 | 500 | 500 | 500 | >1000 | >1000 |
| 6f | 250 | 250 | 500 | 500 | 250 | 500 | >1000 |
| 6g | 62.5 | 200 | 500 | 500 | 1000 | >1000 | 500 |
| 6h | 200 | 500 | 500 | 500 | 1000 | 1000 | 1000 |
| 6i | 500 | 100 | 1000 | 100 | >1000 | 500 | >1000 |
| 6j | 100 | 62.5 | 25 | 100 | 500 | 1000 | 1000 |
| Ampicillin | 100 | 100 | 250 | 100 | – | – | – |
| Griseofulvin | – | – | – | – | 500 | 100 | 100 |
Antibacterial Activity
From the screening results (Table 1), it is evident that compound 1 displayed good to moderate activity against all bacteria (150–250 μg/ml). 2-Amino-6-methylbenzothiazole (2), compound 3 and hydrazide 4 exhibited moderate to poor activity against all bacteria.
The result shows that compounds 5a, 5e, 5j, 6d, 6g and 6j exhibited good activity (25–100 μg/ml) against E. coli; 5d, 5j, 6d, 6i and 6j exhibited good activity (50–100 μg/ml) against P. aeruginosa; 5a, 5e, 5f, 5h, 5j, 6d, 6b and 6j showed good to very good activity (25–150 μg/ml) against S. aureus; whereas 5b, 5h, 5j, 6c, 6i and 6j showed good activity (62.5–100 μg/ml) against S. pyogenes compared with ampicillin. All other compounds showed moderate activity.
Antifungal Activity
From the results of the antifungal activity (Table 1), it is evident that compounds 1, 2, 3 and 4 showed good to moderate activity against C. albicans.
Results also show that Schiff bases and 4-thiazolidinones possessed good activity against C. albicans while moderate activity against A. niger and A. clavatus. Compounds 5a, 5d, 5g, 5j, 6b, 6e, 6f and 6j showed better activity (100–500 μg/ml) against C. albicans when compared with griseofulvin, while all compounds showed poor to moderate activity against A. niger and A. clavatus.
Conclusion
Most of the compounds are comparable with ampicillin. Compounds bearing –Cl, –NO2 groups and furan nucleus are more active than the remaining compounds. Compounds 5a, 5d, 5g, 5j, 6b, 6e, 6f and 6j were found to be active against C. albicans but they found poor with other fungal species.
Experimental
All chemicals were of analytical grade and used directly. Melting points of the synthesized compounds were determined by open tube capillary method and were uncorrected. The purity of the compounds was checked by TLC using Merck silica gel 60 F254. IR spectra were recorded on a Perkin-Elmer RX 1 FTIR spectrophotometer, using potassium bromide pellets; the frequencies are expressed in cm−1. The 1H NMR and 13C NMR spectra were recorded with a Bruker Avance II 400 NMR spectrometer, using TMS as an internal reference, with DMSO-d6 as solvent. The chemical shifts are reported in parts per million (δ ppm). Elemental analyses were performed on Carlo Erba 1180 CHN analyzer. All the results of elemental analyses were in an acceptable error range.
2-Amino-6-methylbenzothiazole (2), 2-[(6-methyl-1,3-benzothiazol-2-yl)amino]nicotinic acid (3) and 2-[(6-methyl-1,3-benzothiazol-2-yl)amino]nicotinohydrazide (4) were prepared by reported procedures [15, 16].
General procedure for syntheses of substituted N’-benzylidene/(2-furylmethylene)-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]nicotinohydrazides (5a–j)
Benzaldehyde (0.012 mole, 1.272 g) and 3–4 drops of glacial acetic acid were added to a solution of 4 (0.01 mole, 3.0 g) in DMF (30 mL). The reaction mixture was refluxed for 5–6 h and monitored by TLC on silica gel using ethyl acetate:toluene (1:3). The reaction mass was cooled and poured onto crushed ice and thus the separated solid was isolated, washed with water and recrystallized from ethanol to give 5a. Other derivatives 5b–j were prepared by the same method.
N’-Benzylidene-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carbohydrazide (5a)
White solid, yield: 52 %, mp: 180–182 °C. IR (KBr) ν cm−1: 3328 (NH), 1645 (amide-I), 1554 (amide-II), 1224 (Amide-III), 1616 (C=N of Schiff base), 2872, 2945 (CH3). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.25 (s, 3H, H-16), 5.84 (s, 1H, H-8), 6.81–8.58 (m, 11H, H-4,5,6,11,13,14,19,20,21,22,23), 8.84 (s, 1H, H-7), 9.34 (s, 1H, H-17); 13C NMR (100MHz, DMSO-d6, TMS): δ 22.1 (C-16), 112.6 (C-3), 118.3 (C-14), 119.8 (C-5), 122.4 (C-11), 127.0 (C-13), 127.9 (C-20,22), 129.9 (C-19,23), 130.9 (C-10), 132.1 (C-21), 134.6 (C-18), 136.9 (C-4), 138.4 (C-12), 143.3 (C-8), 148.2 (C-6), 151.3 (C-15), 161.5 (C-2), 162.1 (C-7), 170.5 (C-9). Anal. Calcd. for C21H17N5OS: C, 65.10; H, 4.43; N, 18.09. Found: C, 65.05; H, 4.38; N, 18.01.
N’-(2-Chlorobenzylidene)-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carbohydrazide (5b)
White solid, yield: 49 %, mp: 168–169 °C. IR (KBr) ν cm−1: 3321 (NH), 1648 (amide-I), 1552 (amide-II), 1223 (amide-III), 1614 (C=N of Schiff base), 2869, 2942 (CH3). 1H NMR (400 MHz, DMSO-d6, TMS): 1.26 (s, 3H, H-16), 5.81 (s, 1H, H-8), 6.81–8.56 (m, 10H, H-4,5,6,11,13,14,19,20,21,22), 8.87 (s, 1H, H-7), 9.36 (s, 1H, H-17). 13C NMR (100MHz, DMSO-d6, TMS): δ 22.3 (C-16), 112.1 (C-3), 118.3 (C-14), 119.6 (C-5), 121.9 (C-11), 126.9 (C-13), 127.1 (C-20), 127.9 (C-19), 130.4 (C-22), 130.8 (C-10), 132.3 (C-21), 133.5 (C-23), 134.9 (C-18), 136.7 (C-4), 137.9 (C-12), 143.5 (C-8), 148.1 (C-6), 150.9 (C-15), 161.7 (C-2), 162.3 (C-7), 170.1 (C-9). Anal. Calcd. for C21H16ClN5OS: C, 59.85; H, 3.83; N, 16.63. Found: C, 59.78; H, 3.75; N, 16.56.
N’-(4-Chlorobenzylidene)-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carbohydrazide (5c)
White solid, yield: 56 %, mp: 156–158 °C. IR (KBr) ν cm−1: 3319 (NH), 1642 (amide-I), 1552 (amide-II), 1223 (amide-III), 1619 (C=N of Schiff base), 2867, 2941 (CH3). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.24 (s, 3H, H-16), 5.82 (s, 1H, H-8), 6.79–8.53 (m, 10H, H-4,5,6,11,13,14,19,20,22,23), 8.86 (s, 1H, H-7), 9.38 (s, 1H, H-17). 13C NMR (100MHz, DMSO-d6, TMS): δ 1.25 (s, 3H, H-16), 5.84 (s, 1H, H-8), 6.81–8.58 (m, 11H, H-4,5,6,11,13,14,19,20,21,22,23), 8.84 (s, 1H, H-7), 9.34 (s, 1H, H-17); 13C NMR (100MHz, DMSO-d6, TMS): δ 22.5 (C-16), 112.8 (C-3), 118.1 (C-14), 119.9 (C-5), 122.1 (C-11), 126.4 (C-13), 128.4 (C-20,22), 130.3 (C-19,23), 131.0 (C-10), 133.9 (C-18), 135.7 (C-21), 137.1 (C-4), 138.3 (C-12), 144.1 (C-8), 147.9 (C-6), 151.1 (C-15), 161.9 (C-2), 163.5 (C-7), 170.4 (C-9). Anal. Calcd. for C21H16ClN5OS: C, 59.85; H, 3.83; N, 16.63. Found: C, 59.79; H, 3.77; N, 16.58.
2-[(6-Methyl-1,3-benzothiazol-2-yl)amino]-N’-(2-nitrobenzylidene)pyridine-3-carbohydrazide (5d)
Yellow solid, yield: 58 %, mp: 188–190 °C. IR (KBr) ν cm−1: 3322 (NH), 1640 (amide-I), 1551 (amide-II), 1221 (amide-III), 1615 (C=N of Schiff base), 2872, 2940 (CH3), 1370, 1512 (NO2). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.23 (s, 3H, H-16), 5.81 (s, 1H, H-8), 6.82–8.56 (m, 10H, H-4,5,6,11,13,14,19,20,21,22), 8.82 (s, 1H, H-7), 9.37 (s, 1H, H-17). 13C NMR (100MHz, DMSO-d6, TMS): δ 22.7 (C-16), 112.7 (C-3), 118.3 (C-14), 119.6 (C-5), 121.9 (C-11), 123.8 (C-22), 126.9 (C-13), 129.8 (C-19), 130.5 (C-10), 132.4 (C-21), 133.9 (C-20), 133.1 (C-18), 137.1 (C-4), 137.9 (C-12), 143.4 (C-8), 147.2 (C-23), 147.4 (C-6), 150.9 (C-15), 161.8 (C-2), 162.0 (C-7), 170.1 (C-9). Anal. Calcd. for C21H16N6O3S: C, 58.32; H, 3.73; N, 19.44. Found: C, 58.26; H, 3.67; N, 19.38.
2-[(6-Methyl-1,3-benzothiazol-2-yl)amino]-N’-(3-nitrobenzylidene)pyridine-3-carbohydrazide (5e)
Yellow solid, yield: 54 %, mp: 176–178 °C. IR (KBr) ν cm−1: 3321 (NH), 1641 (amide-I), 1552 (amide-II), 1226 (amide-III), 1617 (C=N of Schiff base), 2870, 2941 (CH3), 1369, 1511 (NO2). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.27 (s, 3H, H-16), 5.87 (s, 1H, H-8), 6.83–8.56 (m, 10H, H-4,5,6,11,13,14,19,20,21,23), 8.89 (s, 1H, H-7), 9.37 (s, 1H, H-17). 13C NMR (100MHz, DMSO-d6, TMS): δ 22.5 (C-16), 112.6 (C-3), 118.3 (C-14), 119.7 (C-5), 121.1 (C-11), 121.7 (C-23), 126.8 (C-13), 128.9 (C-20), 130.6 (C-10), 131.8 (C-21), 132.9 (C-19), 134.1 (C-18), 137.2 (C-4), 137.8 (C-12), 143.1 (C-8), 147.1 (C-22), 147.1 (C-6), 151.1 (C-15), 161.7 (C-2), 162.8 (C-7), 170.2 (C-9). Anal. Calcd. for C21H16N6O3S: C, 58.32; H, 3.73; N, 19.44. Found: C, 58.26; H, 3.67; N, 19.38.
N’-(4-Hydroxybenzylidene)-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carbohydrazide (5f)
White solid, yield: 61 %, mp: 191–192 °C. IR (KBr) ν cm−1: 3322 (NH), 1644 (amide-I), 1548 (amide-II), 1223 (amide-III), 1618 (C=N of Schiff base), 2868, 2941 (CH3), 3502 (OH). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.26 (s, 3H, H-16), 5.31 (s, 1H, H-24), 5.85 (s, 1H, H-8), 6.82–8.54 (m, 10H, H-4,5,6,11,13,14,19,20,22,23), 8.79 (s, 1H, H-7), 9.31 (s, 1H, H-17). 13C NMR (100MHz, DMSO-d6, TMS): δ 1.25 (s, 3H, H-16), 5.84 (s, 1H, H-8), 6.81–8.58 (m, 11H, H-4,5,6,11,13,14,19,20,21,22,23), 8.84 (s, 1H, H-7), 9.34 (s, 1H, H-17); 13C NMR (100MHz, DMSO-d6, TMS): δ 22.6 (C-16), 112.4 (C-3), 117.9 (C-20,22), 118.3 (C-14), 119.8 (C-5), 122.3 (C-11), 126.9 (C-13), 130.1 (C-19,23), 130.9 (C-10), 132.9 (C-18), 136.9 (C-4), 138.1 (C-12), 143.2 (C-8), 147.9 (C-6), 151.3 (C-15), 161.6 (C-2), 158.1 (C-21), 163.3 (C-7), 170.2 (C-9). Anal. Calcd. for C21H17N5O2S: C, 62.51; H, 4.25; N, 17.37. Found: C, 62.45; H, 4.18; N, 17.30.
N’-(4-Methoxybenzylidene)-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carbohydrazide (5g)
Brown solid, yield: 59 %, mp: 170–171 °C. IR (KBr) ν cm−1: 3321 (NH), 1643 (amide-I), 1555 (amide-II), 1228 (amide-III), 1615 (C=N of Schiff base), 2873, 2939 (CH3), 1039, 1179 (OCH3). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.28 (s, 3H, H-16), 3.88 (s, 1H, H-24), 5.81 (s, 1H, H-8), 6.86–8.58 (m, 10H, H-4,5,6,11,13,14,19,20,22,23), 8.86 (s, 1H, H-7), 9.34 (s, 1H, H-17). 13C NMR (100MHz, DMSO-d6, TMS): δ 21.9 (C-16), 55.1 (C-24), 113.1 (C-3), 115.9 (C-20,22), 118.3 (C-14), 119.7 (C-5), 121.9 (C-11), 127.1 (C-13), 129.8 (C-19,23), 131.0 (C-10), 131.9 (C-18), 136.9 (C-4), 137.1 (C-12), 142.9 (C-8), 148.0 (C-6), 151.1 (C-15), 160.8 (C-2), 162.0 (C-21), 163.1 (C-7), 170.0 (C-9). Anal. Calcd. for C22H19N5O2S: C, 63.29; H, 4.59; N, 16.79. Found: C, 63.23; H, 4.50; N, 16.70.
N’-(4-Hydroxy-3-methoxybenzylidene)-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carbohydrazide (5h)
White solid, yield: 64 %, mp: 145–146 °C. IR (KBr) ν cm−1: 3323 (NH), 1645 (amide-I), 1554 (amide-II), 1221 (amide-III), 1616 (C=N of Schiff base), 2874, 2942 (CH3), 3507 (OH). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.26 (s, 3H, H-16), 3.86 (s, 3H, H-24), 5.38 (s, 1H, H-25), 5.80 (s, 1H, H-8), 6.83–8.58 (m, 9H, H-4,5,6,11,13,14,19,20,23), 8.87 (s, 1H, H-7), 9.36 (s, 1H, H-17). 13C NMR (100MHz, DMSO-d6, TMS): δ 22.2 (C-16), 55.9 (C-24), 110.9 (C-23), 112.7 (C-3), 116.7 (C-20), 118.3 (C-14), 119.2 (C-5), 121.9 (C-11), 122.4 (C-19), 127.0 (C-13), 130.9 (C-10), 132.1 (C-18), 137.4 (C-4), 138.1 (C-12), 143.1 (C-8), 147.8 (C-6), 149.1 (C-22), 150.9 (C-15), 152.8 (C-21), 161.2 (C-2), 163.5 (C-7), 170.2 (C-9). Anal. Calcd. for C22H19N5O3S: C, 60.95; H, 4.42; N, 16.17. Found: C, 60.88; H, 4.36; N, 16.10.
N’-(4-Hydroxy-3-methoxy-5-nitrobenzylidene)-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carbohydrazide (5i)
Yellow solid, yield: 48 %, mp: 198–199 °C. IR (KBr) ν cm−1: 3324 (NH), 1647 (amide-I), 1552 (amide-II), 1225 (amide-III), 1618 (C=N of Schiff base), 2871, 2939 (CH3), 1037, 1181 (OCH3), 3503 (OH). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.26 (s, 3H, H-16), 3.87 (s, 3H, H-24), 5.32 (s, 1H, H-25), 5.84 (s, 1H, H-8), 6.82–8.56 (m, 8H, H-4,5,6,11,13,14,19,23), 8.87 (s, 1H, H-7), 9.37 (s, 1H, H-17). 13C NMR (100MHz, DMSO-d6, TMS): δ 22.5 (C-16), 55.7 (C-24), 112.6 (C-3), 117.4 (C-19), 118.0 (C-23), 118.3 (C-14), 119.7 (C-5), 121.9 (C-11), 127.0 (C-13), 129.1 (C-18), 130.6 (C-10), 136.7 (C-20), 137.4 (C-4), 138.2 (C-12), 140.8 (C-21), 143.3 (C-8), 147.7 (C-6), 150.5 (C-15), 151.7 (C-22), 161.5 (C-2), 163.1 (C-7), 170.5 (C-9). Anal. Calcd. for C22H18N6O5S: C, 55.22; H, 3.79; N, 17.57. Found: C, 55.16; H, 3.70; N, 17.50.
N’-(Furan-2-ylmethylidene)-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carbohydrazide (5j)
Black solid, yield: 54 %, mp: 181–184 °C, IR (KBr) ν cm−1: 3320 (NH), 1646 (amide-I), 1553 (amide-II), 1223 (amide-III), 1617 (C=N of Schiff base), 2869, 2941 (CH3). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.27 (s, 3H, H-16), 5.81 (s, 1H, H-8), 6.86–8.52 (m, 9H, H-4,5,6,11,13,14,19,20,21), 8.86 (s, 1H, H-7), 9.38 (s, 1H, H-17). 13C NMR (100MHz, DMSO-d6, TMS): δ 22.7 (C-16), 112.6 (C-3), 113.3 (C-20), 116.9 (C-14), 118.1(C-19), 119.8 (C-5), 121.1 (C-11), 126.3 (C-13), 130.6 (C-10), 133.3 (C-8), 136.7 (C-4), 137.4 (C-12), 143.7 (C-21), 147.2 (C-6), 148.4 (C-18), 150.3 (C-15), 161.5 (C-2), 162.7 (C-7), 170.2 (C-9). Anal. Calcd. for C19H15N5O2S: C, 60.46; H, 4.01; N, 18.57. Found: C, 60.39; H, 3.94; N, 18.50.
General procedure for syntheses of 2-[(6-methyl-1,3-benzothiazol-2-yl)amino]-N-[2-(substituted phenyl/furan-2-yl)-4-oxo-1,3-thiazolidin-3-yl]pyridine-3-carboxamides (6a–j)
A mixture of 5a (0.01 mole, 3.87 g), thioglycolic acid (0.015 mole, 1.38 g) and a pinch of anhydrous ZnCl2 in dry 1,4-dioxane (30 mL) was refluxed for 12–14 h. The reaction was monitored by TLC on silica gel using ethyl acetate: toluene (1:3); was cooled and neutralized with 10% sodium bicarbonate solution. The solid product separated was filtered, washed with water and recrystallized from ethanol to give 6a. Similarly, other 2-[(6-methyl-1,3-benzothiazol-2-yl)amino]-N-[2-(substituted phenyl/furan-2-yl)-4-oxo-1,3-thiazolidin-3-yl]pyridine-3-carboxamides 6b–j have been prepared by the same method.
2-[(6-Methyl-1,3-benzothiazol-2-yl)amino]-N-(4-oxo-2-phenyl-1,3-thiazolidin-3-yl)pyridine-3-carboxamide (6a)
White solid, yield: 57 %, mp: 184–186 °C. IR (KBr) ν cm−1: 3321 (NH), 1715 (C=O of 4-thiazolidinone), 1646 (amide-I), 1556 (amide-II), 1224 (amide-III), 2878, 2950 (CH3). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.24 (s, 3H, H-18), 3.63 (s, 2H, H-9), 6.21 (s, 1H, H-10), 6.91–8.57 (m, 11H, H-4,5,6,13,15,16,21,22,23,24,25), 8.91 (s, 1H, H-7), 9.36 (s, 1H, H-19). 13C NMR (100MHz, DMSO-d6, TMS): δ 21.1 (C-18), 35.9 (C-9), 57.7 (C-10), 111.6 (C-3), 114.1 (C-16), 118.5 (C-5), 121.1 (C-13), 125.9 (C-15), 127.1 (C-22,24), 128.1 (C-21,25), 129.9 (C-12), 134.4 (C-14), 137.0 (C-4), 138.1 (C-20), 147.4 (C-6), 149.1 (C-17), 127.9 (C-23), 163.5 (C-2), 163.1 (C-7), 169.3 (C-8), 171.2 (C-11). Anal. Calcd. for C23H19N5O2S2: C, 59.86; H, 4.15; N, 15.18. Found: C, 59.80; H, 4.08; N, 15.12.
N-[2-(2-Chlorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carboxamide (6b)
White solid, yield: 63 %, mp: 196–197 °C. IR (KBr) ν cm−1: 3322 (NH), 1718 (C=O of 4-thiazolidinone), 1644 (amide-I), 1555 (amide-II), 1225 (amide-III), 2875, 2948 (CH3), 755 (C-Cl). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.25 (s, 3H, H-18), 3.63 (s, 2H, H-9), 6.20 (s, 1H, H-10), 6.89–8.58 (m, 10H, H-4,5,6,13,15,16,21,22,23,24), 8.93 (s, 1H, H-7), 9.33 (s, 1H, H-19). 13C NMR (100MHz, DMSO-d6, TMS): δ 23.7 (C-18), 35.7 (C-9), 57.8 (C-10), 102.9 (C-20), 111.2 (C-3), 116.9 (C-16), 119.1 (C-5), 120.9 (C-13), 126.1 (C-15), 126.4 (C-22), 127.9 (C-24), 128.4 (C-23), 129.9 (C-12), 130.1 (C-21), 133.8 (C-25), 134.4 (C-14), 137.1 (C-4), 147.2 (C-6), 149.7 (C-17), 163.4 (C-7), 163.7 (C-2), 169.2 (C-8), 171.3 (C-11). Anal. Calcd. for C23H18ClN5O2S2: C, 55.75; H, 3.66; N, 14.14. Found: C, 55.70; H, 3.59; N, 14.06.
N-[2-(4-Chlorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carboxamide (6c)
White solid, yield: 60 %, mp: 209–210 °C. IR (KBr) ν cm−1: 3323 (NH), 1716 (C=O of 4-thiazolidinone), 1646 (amide-I), 1560 (amide-II), 1226 (amide-III), 2872, 2946 (CH3), 756 (C-Cl). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.23 (s, 3H, H-18), 3.65 (s, 2H, H-9), 6.26 (s, 1H, H-10), 6.92–8.56 (m, 10H, H-4,5,6,13,15,16,21,22,24,25), 8.91 (s, 1H, H-7), 9.34 (s, 1H, H-19). 13C NMR (100MHz, DMSO-d6, TMS): δ 23.4 (C-18), 35.4 (C-9), 57.6 (C-10), 111.4 (C-3), 116.9 (C-16), 118.4 (C-5), 121.1 (C-13), 125.9 (C-15), 127.6 (C-22,24), 129.2 (C-21,25), 129.9 (C-12), 132.1 (C-23), 134.0 (C-14), 135.1 (C-20), 137.0 (C-4), 147.3 (C-6), 150.1 (C-17), 163.2 (C-7), 163.8 (C-2), 169.7 (C-8), 171.0 (C-11). Anal. Calcd. for C23H18ClN5O2S2: C, 55.75; H, 3.66; N, 14.14. Found: C, 55.69; H, 3.61; N, 14.07.
2-[(6-Methyl-1,3-benzothiazol-2-yl)amino]-N-[2-(2-nitrophenyl)-4-oxo-1,3-thiazolidin-3-yl]pyridine-3-carboxamide (6d)
Yellow solid, yield: 56 %, mp: 219–221 °C. IR (KBr) ν cm−1: 3319 (NH), 1718 (C=O of 4-thiazolidinone), 1644 (amide-I), 1554 (amide-II), 1224 (amide-III), 2871, 2945 (CH3), 1371, 1514 (NO2). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.25 (s, 3H, H-18), 3.62 (s, 2H, H-9), 6.21 (s, 1H, H-10), 6.87–8.57 (m, 10H, H-4,5,6,13,15,16,21,22,23,24), 8.92 (s, 1H, H-7), 9.35 (s, 1H, H-19). 13C NMR (100MHz, DMSO-d6, TMS): δ 23.6 (C-18), 35.6 (C-9), 57.1 (C-10), 111.3 (C-3), 116.5 (C-16), 118.7 (C-5), 120.9 (C-13), 124.1 (C-24), 125.9 (C-15), 127.3 (C-23), 128.9 (C-21), 129.9 (C-12), 132.6 (C-22), 133.5 (C-20), 134.4 (C-14), 137.1 (C-4), 147.3 (C-6), 148.6 (C-25), 149.8 (C-17), 163.1 (C-7), 163.6 (C-2), 169.4 (C-8), 171.1 (C-11). Anal. Calcd. for C23H18N6O4S2: C, 54.54; H, 3.58; N, 16.60. Found: C, 54.48; H, 3.50; N, 16.56.
2-[(6-Methyl-1,3-benzothiazol-2-yl)amino]-N-[2-(3-nitrophenyl)-4-oxo-1,3-thiazolidin-3-yl]pyridine-3-carboxamide (6e)
Yellow solid, yield: 52 %, mp: 213–214 °C. IR (KBr) ν cm−1: 3318 (NH), 1714 (C=O of 4-thiazolidinone), 1648 (amide-I), 1560 (amide-II), 1227 (amide-III), 2869, 2946 (CH3), 1365, 1510 (NO2). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.21 (s, 3H, H-18), 3.60 (s, 2H, H-9), 6.24 (s, 1H, H-10), 6.96–8.59 (m, 10H, H-4,5,6,13,15,16,21,22,23,25), 8.90 (s, 1H, H-7), 9.34 (s, 1H, H-19). 13C NMR (100MHz, DMSO-d6, TMS): δ 23.4 (C-18), 35.7 (C-9), 57.1 (C-10), 111.3 (C-3), 116.5 (C-16), 119.1 (C-5), 121.2 (C-13), 122.1 (C-23), 123.6 (C-22), 125.2 (C-25), 126.1 (C-15), 129.7 (C-12), 133.1 (C-21), 134.0 (C-14), 137.1 (C-4), 140.0 (C-20), 146.4 (C-24), 147.9 (C-6), 149.7 (C-17), 163.1 (C-7), 163.4 (C-2), 169.2 (C-8), 171.3 (C-11). Anal. Calcd. for C23H18N6O4S2: C, 54.54; H, 3.58; N, 16.60. Found: C, 54.47; H, 3.51; N, 16.55.
N-[2-(4-Hydroxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carboxamide (6f)
Brown solid, yield: 57 %, mp: 236–238 °C. IR (KBr) ν cm−1: 3320 (NH), 1717 (C=O of 4-thiazolidinone), 1646 (Aamide-I), 1556 (amide-II), 1228 (amide-III), 2872, 2942 (CH3), 3506 (OH). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.24 (s, 3H, H-18), 3.61 (s, 2H, H-9), 5.30 (s, 1H, H-26), 6.19 (s, 1H, H-10), 6.86–8.52 (m, 10H, H-4,5,6,13,15,16,21,22,24,25), 8.90 (s, 1H, H-7), 9.36 (s, 1H, H-19). 13C NMR (100MHz, DMSO-d6, TMS): δ 23.2 (C-18), 35.5 (C-9), 57.3 (C-10), 111.3 (C-3), 114.7 (C-16), 115.6 (C-22,24), 118.6 (C-5), 121.0 (C-13), 125.9 (C-15), 129.8 (C-12), 130.3 (C-21,25), 131.6 (C-20), 134.3 (C-14), 136.9 (C-4), 147.8 (C-6), 149.7 (C-17), 156.8 (C-23), 163.1 (C-2), 163.7 (C-7), 169.4 (C-8), 171.4 (C-11). Anal. Calcd. for C23H19N5O3S2: C, 57.85; H, 4.01; N, 14.68. Found: C, 57.78; H, 3.94; N, 14.60.
N-[2-(4-Methoxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carboxamide (6g)
Brown solid, yield: 51 %, mp: 249–251 °C. IR (KBr) ν cm−1: 3321 (NH), 1719 (C=O of 4-thiazolidinone), 1648 (amide-I), 1552 (amide-II), 1227 (amide-III), 2873, 2947 (CH3), 1036, 1189 (OCH3). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.24 (s, 3H, H-18), 3.64 (s, 2H, H-9), 3.82 (s, 3H, H-26), 6.23 (s, 1H, H-10), 6.93–8.55 (m, 10H, H-4,5,6,13,15,16,21,22,24,25), 8.92 (s, 1H, H-7), 9.35 (s, 1H, H-19). 13C NMR (100MHz, DMSO-d6, TMS): δ 21.7 (C-18), 35.5 (C-9), 55.2 (C-26), 59.6 (C-10), 111.9 (C-3), 112.6 (C-22,24), 114.5 (C-16), 118.7 (C-5), 120.9 (C-13), 125.8 (C-15), 128.9 (C-21,25), 129.8 (C-12), 130.9 (C-20), 134.4 (C-14), 136.8 (C-4), 148.1 (C-6), 149.3 (C-17), 157.9 (C-23), 163.3 (C-2), 164.6 (C-7), 169.4 (C-8), 171.5 (C-11). Anal. Calcd. for C24H21N5O3S2: C, 58.64; H, 4.34; N, 14.26. Found: C, 58.58; H, 4.29; N, 14.18.
N-[2-(4-Hydroxy-3-methoxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carboxamide (6h)
White solid, yield: 53 %, mp: 225–226 °C. IR (KBr) ν cm−1: 3318 (NH), 1718 (C=O of 4-thiazolidinone), 1647 (amide-I), 1556 (amide-II), 1224 (amide-III), 2876, 2944 (CH3), 1034, 1191 (OCH3), 3510 (OH). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.22 (s, 3H, H-18), 3.63 (s, 2H, H-9), 3.87 (s, 1H, H-26), 5.32 (s, 1H, H-27), 6.21 (s, 1H, H-10), 6.90–8.58 (m, 9H, H-4,5,6,13,15,16,21,22,25), 8.94 (s, 1H, H-7), 9.32 (s, 1H, H-19). 13C NMR (100MHz, DMSO-d6, TMS): δ 23.8 (C-18), 35.4 (C-9), 55.9 (C-26), 57.6 (C-10), 111.1 (C-3), 114.1 (C-25), 114.7 (C-16), 115.6 (C-22), 118.9 (C-5), 121.1 (C-13), 122.1 (C-21), 125.9 (C-15), 130.1 (C-12), 131.8 (C-20), 134.1 (C-14), 137.1 (C-4), 146.9 (C-24), 147.2 (C-23), 147.9 (C-6), 149.7 (C-17), 163.7 (C-2), 164.7 (C-7), 168.9 (C-8), 171.2 (C-11). Anal. Calcd. for C24H21N5O4S2: C, 56.79; H, 4.17; N, 13.81. Found: C, 56.71; H, 4.11; N, 13.73.
N-[2-(4-Hydroxy-3-methoxy-5-nitrophenyl)-4-oxo-1,3-thiazolidin-3-yl]-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carboxamide (6i)
Yellow solid, yield: 59 %, mp: 256–257 °C. IR (KBr) ν cm−1: 3511 (OH), 3321 (NH), 1715 (C=O of 4-thiazolidinone), 1646 (Amide-I), 1561 (Amide-II), 1226 (Amide-III), 2877, 2947 (CH3), 1035, 1192 (OCH3). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.23 (s, 3H, H-18), 3.62 (s, 2H, H-9), 3.85 (s, 1H, H-26), 5.35 (s, 1H, H-27), 6.20 (s, 1H, H-10), 6.87–8.56 (m, 8H, H-4,5,6,13,15,16,21,25), 8.91 (s, 1H, H-7), 9.34 (s, 1H, H-19). 13C NMR (100MHz, DMSO-d6, TMS): δ 23.4 (C-18), 35.7 (C-9), 55.7 (C-26), 57.3 (C-10), 111.7 (C-3), 116.9 (C-16), 118.8 (C-5,21), 120.2 (C-25), 121.1 (C-13), 125.9 (C-15), 130.1 (C-12), 132.9 (C-20), 134.0 (C-14), 136.2 (C-23), 136.9 (C-4), 137.6 (C-22), 147.8 (C-6), 149.7 (C-17), 152.1 (C-24), 163.5 (C-7), 163.8 (C-2), 169.7 (C-8), 171.6 (C-11). Anal. Calcd. for C24H20N6O6S2: C, 52.17; H, 3.65; N, 15.22. Found: C, 52.10; H, 3.58; N, 15.15.
N-[2-(Furan-2-yl)-4-oxo-1,3-thiazolidin-3-yl]-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]pyridine-3-carboxamide (6j)
Black solid, yield: 59 %, mp: 223–225 °C. IR (KBr) ν cm−1: 3419 (NH), 1715 (C=O of 4-thiazolidinone), 1645 (amide-I), 1558 (amide-II), 1225 (amide-III), 2874, 2948 (CH3). 1H NMR (400 MHz, DMSO-d6, TMS): δ 1.22 (s, 3H, H-18), 3.60 (s, 2H, H-9), 6.20 (s, 1H, H-10), 6.78–8.51 (m, 9H, H-4,5,6,13,15,16,21,22,23), 8.91 (s, 1H, H-7), 9.34 (s, 1H, H-19). 13C NMR (100MHz, DMSO-d6, TMS): δ 23.8 (C-18), 35.0 (C-9), 57.1 (C-10), 105.4 (C-22),109.7 (C-21), 111.2 (C-3), 116.5 (C-16), 118.9 (C-5), 121.1 (C-13), 125.9 (C-15), 130.1 (C-12), 134.0 (C-14), 137.0 (C-4), 141.5 (C-23), 147.3 (C-6), 149.7 (C-17), 151.1 (C-20), 163.1 (C-2), 163.8 (C-7), 169.1 (C-8), 170.9 (C-11). Anal. Calcd. for C21H17N5O3S2: C, 55.87; H, 3.80; N, 15.52. Found: C, 55.80; H, 3.72; N, 15.45.
Experimental protocol for Antimicrobial activity
All the compounds were tested for their antibacterial and antifungal activity (MIC) in vitro by broth dilution method against two Gram positive S. aureus MTCC 96, S. pyogenes MTCC 442 and two Gram negative E. coli MTCC 443, P. aeruginosa MTCC 741 bacteria and three fungal species C. albicans MTCC 227, A. niger MTCC 282 and A. clavatus MTCC 1323. Ampicillin for antibacterial activity while griseofulvin for antifungal activity were used as a standard drug
The experimental protocol followed for antimicrobial activity was according to the same method as previously reported in literature [18, 19].
Fig. 1.
Numbering of substituted N’-benzylidene/(2-furylmethylene)-2-[(6-methyl-1,3-benzothiazol-2-yl)amino]nicotinohydrazides 5a–j
Fig. 2.
Numbering of 4-Thiazolidinones 6a–j
Acknowledgments
The authors thank to Professor and Head, Department of Chemistry, VNSGU, Surat for providing necessary laboratory facilities, Microcare laboratory, Surat for antimicrobial activity, SAIF, Chandigarh for IR, 1H-NMR and 13C-NMR spectral analyses, SAIF, Lucknow for elemental analyses and Atul Limited, Atul for providing some free samples. One of us, Faiyazalam M. Shaikh is thankful to UGC, New Delhi for Maulana Azad National Fellowship.
Authors’ Statement
Competing Interests
The authors declare no conflict of interest.
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