Design, synthesis, and biological evaluation studies of novel thiophene substituted thiazolidinones scaffold as promising antimicrobial agents

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The outcomes are to be compared with typical drugs given that compounds are examined against gram-positive and gram-negative strains of bacteria and fungus. Against bacterial strains, products with nitro, methyl, and bromo substituents in the p-position of the benzene ring, as well as products with the nitro group at the m-position, showed very excellent activities against bacterial strains, while compounds with chloro substituent at p-position and m-position demonstrated good activity against the fungal strains Aspergillus niger and Fusarium javanicum.

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Nội dung Text: Design, synthesis, and biological evaluation studies of novel thiophene substituted thiazolidinones scaffold as promising antimicrobial agents

Received: 8 April 2023 Revised: 14 June 2023 Accepted: 12 August 2023 DOI: 10.1002/vjch.202300116 RESEARCH ARTICLE Design, synthesis, and biological evaluation studies of novel thiophene substituted thiazolidinones scaffold as promising antimicrobial agents Dinesh R. Godhani Umang P. Mehta Jignasu P. Mehta Anwar H. Saiyad Department of Chemistry (DST-FIST sponsored Department), Mahatma Gandhi Campus, Abstract Maharaja Krishnakumarsinhji Bhavnagar Global public health is profoundly imperiled by antimicrobial resistance (AMR) and University, Bhavnagar, India has made it extremely difficult to effectively control infectious diseases which are connected to it, so a new series of 5-benzylidene-2-(thiophen-2-yl)-3-(4H-1,2,4- Correspondence Dinesh R. Godhani, Department of Chemistry, triazol-4-yl)thiazolidin-4-ones (5a–o) is synthesized. Spectral techniques have Mahatma Gandhi Campus, Maharaja been utilized to characterize and confirm the structures of targeted molecules. Krishnakumarsinhji Bhavnagar University, The outcomes are to be compared with typical drugs given that compounds are Bhavnagar 364002, India. Email: drgodhani@mkbhavuni.edu.in examined against gram-positive and gram-negative strains of bacteria and fun- gus. Against bacterial strains, products with nitro, methyl, and bromo substituents Funding information in the p-position of the benzene ring, as well as products with the nitro group Department of Chemistry and Maharaja at the m-position, showed very excellent activities against bacterial strains, while Krishnakumarsinhji Bhavnagar University compounds with chloro substituent at p-position and m-position demonstrated good activity against the fungal strains Aspergillus niger and Fusarium javanicum. KEYWORDS 1, 2, 4-triazole, antimicrobial activity, thiazolidinone, thiophene 1 INTRODUCTION many biological activities. One of the main moieties of medicinal compounds that satisfy novel drug discovery In dealing with of a range of biological activities, the needs is 1,2,4-triazoles.8,9 Depending on how replace- recent appearance of heterocyclic moieties is crucial.1,2 ments are arranged around the ring, the 1,2,4-triazole Pathogenic infections caused by microbial diseases repre- represents an important class of compounds with an exten- sent a serious threat to worldwide wellness and seriously sive range of biological activity.10–13 1,2,4-triazoles are impair global healthcare systems. Furthermore, growing a considerable class of organic compounds with a vari- medication resistance exacerbates the issue. The structural ety of biological activities, including antimalarial,14 anti- skeleton of sulfur-containing heterocycles is dominated by leishmanial,15 anti-urease,16 antiviral,17 anticonvulsant,18 thiophene.3,4 It is among the most important therapeu- and other properties. The effectiveness of a novel drug is tic groups of antibacterial used globally to treat bacterial apparently based on the design of the targeted molecule. and drug-resistant diseases.5 The ongoing need to supple- Piprozolin has been selected as a commercially avail- ment and diversify existing treatments with novel potential able drug to design the molecule (5a–o). A piperidine agents that exhibit improved efficacy and activity, higher moiety and 4-thiazolidinone have been found present in idiosyncrasy, and reduced fatalness has spurred the use of piprozolin. It also possesses an ester and ethyl group on thiophene moiety in biologically relevant compounds.6,7 the second and third position of 4-thiazolidinone moi- Only a brief, unstructured section is devoted to thiophene- ety respectively.19,20 The biological effects of thiazolidin- containing compounds with antibacterial action because 4-ones are well documented to include antibacterial, thiophenes are pharmacologically significant scaffolds for antifungal, antiviral, anti-inflammatory, and antitubercular © 2024 Vietnam Academy of Science and Technology and Wiley-VCH GmbH. Vietnam J. Chem. 2024;62:133–140. wileyonlinelibrary.com/journal/vjch 133
25728288, 2024, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300116 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 134 GODHANI ET AL. action.21,22 4-Thiazolidinone moiety of the piprozolin drug 2.2 General procedure for synthesis of is unchanged and we have modified its second, third, and 2-(thiophen-2-yl)−3-(4H-1,2,4-triazol-4- fifth position. Ester at second position and ethyl group at yl)thiazolidin-4-one (4) third position of 4-thiazolidinone is replaced by thiophene moiety and triazole moiety respectively. Moreover, piperi- Thioglycolic acid (0.01 mol) was injected after compound dine at the fifth position is replaced by substituted phenyl 3 (0.01 mol) was mixed in dimethyl formamide (20 mL). The rings. In this work, a range of new hybrid compounds, reaction was catalyzed by anhydrous ZnCl2 , and the mixture including those with thiophene and 1,2,4-triazole moieties, was refluxed at 120−140 ◦ C for 12–14 h. After the reaction were created and synthesized. The antibacterial potency of mixture had reached room temperature, it had been poured these hybrids was then investigated. into crushed ice. Once the reaction was neutralized using a saturated NaHCO3 solution, a product was formed. To get compound (4), The product was dried, recrystallized with 2 MATERIALS AND METHODS ethanol, and rinsed with cold distilled water. Yield 61%, m.p. 182–184 ◦ C. IR spectrum, ν, cm−1 : All of the initial materials and reagents were proffered by 798 (C─S), 1129 (─N─N─), 1519 (─C─N), 1619 (─C═N─), Sigma-Aldrich, Merck, and Loba Chemical. Thin layer chro- 1724(C═O), 3038 (C─H). 1 H NMR spectrum (500 MHz, matography (TLC) on silica gel plates was used to check the DMSO-d6 ), δ, ppm:, 3.76 s (2H, CH2 , thiazolidinone ring), purity and monitor the reaction (Merck, 60, F254). Melting 5.92 s(1H, CH─N, thiazolidinone ring), 6.99 t (J = 7.5 Hz, 1H, points were measured in open capillaries on an electrical C═CH, thiophene ring), 7.05–7.11 m (1H), 7.39 d (J = 7.4 Hz, melting point apparatus and are uncorrected. The elemen- 1H, S─CH, thiophene ring), 8.57 s (2H, CH─N─CH, tri- tal analysis (% C, H, N) was performed using a PerkinElmer azole ring). 13 C NMR spectrum (125 MHz, DMSO-d6 ) δ, 2400 CHN analyzer. IR spectra of all synthesized compounds ppm: 34.52, 62.55, 125.98, 127.25, 128.18, 140.92, 142.34, were recorded in KBr using a PerkinElmer FT-IR spectropho- 169.51. MS: m/z: 357.10 [M+H]+ : 253.06. Found, %: C-42.84; tometer. Tetramethyl silane (TMS) was used as an internal H-3.20; N-22.21. C9 H8 N4 OS2 . Calcd., %: C-42.87; H-3.27; standard, and 1 H and 13 C were recorded using a Var- N-22.24. ian Gemini 500 MHz NMR instrument. Chemical shifts are reported in parts per million (δ in ppm). To scan the mass spectra of synthesized compounds, a Shimadzu LC-MS 2010 2.3 Preparation of 5-arylidine-2- spectrometer was employed. (thiophen-2-yl)−3-(4H-1,2,4-triazol-4-yl) thiazolidin-4-ones (5a–o) 2.1 General procedure for synthesis of Ethanol was used to dissolve compound 4 (0.01 mol), 1-(thiophen-2-yl)-N-(4H-1,2,4-triazol-4-yl) and different aromatic aldehydes (0.01 mol) were added. methanimine (3) Sodium ethoxide was used in this reaction in a catalytic quantity. The reaction mixture has been refluxed at 50– 1,2,4-triazol-4-amine 2 (0.01 mol) and thiophene-2- 60 ◦ C for 4–6 h. After completion of the reaction. The carbaldehyde (1) (0.01 mol) were mixed in ethanol until a desired compounds (5a–o) were obtained by pouring the homogeneous mixture was obtained. The reaction mixture reaction mixture over crushed ice and allowing it to cool was catalytically added with CH3 COOH, and then heated at ambient temperature. The generated product undergoes and stirred at 60–80 ◦ C for 6–8 h. Following a reaction check filtering, distilled water washing, vacuum oven drying, and employing thin-layer chromatography, the reaction mass recrystallization. was allowed to cool at room temperature before being 5-benzylidene-2-(thiophen-2-yl)−3-(4H-1,2,4-triazol-4-yl) poured into cold water to generate an intermediate (3). thiazolidin-4-one (5a): Yield 72%, m.p. 140–142 ◦ C. IR spec- The product was dried, recrystallized from ethanol. trum, ν, cm−1 : 678 (C─S), 1164 (─N─N─), 1534 (─C─N), Yield 74%, m.p. 135–137 ◦ C. IR spectrum, ν, cm−1 : 794 1627 (─C═N─), 1741 (C═O), 3025 (C─H). 1 H NMR spectrum (C─S), 1127 (─N─N─), 1524 (─C─N), 1618 (─C═N─), 3038 (500 MHz, DMSO-d6 ), δ, ppm: 6.29 d (1H, J = 0.6 Hz, CH, (C─H). 1 H NMR spectrum (500 MHz, DMSO-d6 ), δ, ppm: thiazolidinedione ring), 6.99 t (1H, J = 7.4 Hz, C═CH─C, 7.11 t (1H, J = 7.5 Hz, C─CH═C, thiophene ring), 7.52 d thiophene ring), 7.04 d (1H, J = 7.5 Hz, C─CH, thiophene (1H, J = 7.5 Hz, CH─C═C, thiophene ring), 7.66 d (1H, ring), 7.33–7.40 m (2H, HAr ), 7.40–7.47 m (2H, C═CH), J = 7.5 Hz, C─C═CH, thiophene ring), 8.76 s (1H, CH═N), 7.58–7.63 m (2H, HAr ),7.76 s (1H, C═CH─Ar), 8.55 s (2H, 8.95 s (2H, CH─N─CH, triazole ring), 13 C NMR spectrum CH─N─CH, triazole ring). 13 C NMR spectrum (125 MHz, (125 MHz, DMSO-d6 ) δ, ppm: 127.57, 128.77, 131.05, 134.82, D DMSO-d6 ) δ, ppm: 62.32, 122.19, 126.26 127.27, 127.82, 138.03, 141.87. MS: m/z: 357.10 [M+H]+ : 179.12. Found, 129, 129.45, 129.6, 131.62, 133.96, 138.19, 141.34, 166.8. MS: %: C-47.18, H-3.39, N-31.44. C7 H6 N4 S. Calcd., %: C-47.15, m/z: 341.14 [M+H]+ . Found, %: C-56.45; H-3.55; N-16.46. H-3.37, N-31.42. C16 H12 N4 OS2 . Calcd., %: C-56.42; H-3.51; N-16.42.
25728288, 2024, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300116 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License GODHANI ET AL. 135 5-(2-hydroxybenzylidene)−2-(thiophen-2-yl)−3-(4H-1,2, 8.05–8.11 m (2H, HAr ), 8.56 s (2H, CH─N─CH, triazole ring). 4-triazol-4-yl)thiazolidin-4-one (5b): Yield 68%, m.p. 156– 13 C NMR spectrum (125 MHz, DMSO-d ) δ 62.30, 122.14, 6 158 ◦ C. IR spectrum, ν, cm−1 : 691 (C─S), 1118 (─N─N─), 124.34, 125.96, 127.27, 128.15, 129.68, 131.54, 135.92, 1541 (─C─N), 1613 (─C═N─), 1715 (C═O), 3017 (C─H), 137.85, 141.33, 147.88, 166.79. MS: m/z: 386.05 [M+H]+ . 3244 (C─OH).1 H NMR spectrum (500 MHz, DMSO-d6 ), Found, %: C-49.86; H-2.88; N-15.72. C16 H11 N5 O3 S2 . Calcd., δ, ppm: 6.23 d (1H, J = 0.6 Hz, CH, thiazolidinone ring), %: C-49.84; H-2.85; N-15.71. 6.88–6.97 m (2H, HAr ), 7.00 t (1H, J = 7.4 Hz, C═CH─C, 5-(3-nitrobenzylidene)−2-(thiophen-2-yl)−3-(4H-1,2,4- thiophene ring), 7.02–7.07 m (1H, C─CH, thiophene ring), triazol-4-yl)thiazolidin-4-one (5f): Yield 61%, m.p. 180– 7.31 t (1H, J = 7.5 Hz, HAr ), 7.36 d (1H, J = 7.3 Hz, S─CH, 182 ◦ C. IR spectrum, ν, cm−1 : 727 (C─S), 1169 (─N─N─), thiophene ring), 7.47 d (J = 1.5 Hz, 1H, HAr ), 7.95 s (1H, 1371 (C─NO2 ), 1526 (─C─N), 1635 (─C═N─), 1744 (C═O), CH═C), 8.55 s (2H, CH─N─CH, triazole ring), 9.67 s (1H, 3029 (C─H). 1 H NMR spectrum (500 MHz, DMSO-d6 ) δ, ppm Ar─OH). 13 C NMR spectrum (125 MHz, DMSO-d6 ) δ, ppm: 6.29 d (1H, J = 0.6 Hz, CH, thiazolidinone ring), 7.00 t (1H, 62.30, 116.09, 121.01, 122.60, 124.50, 126.06, 127.27, J = 7.4 Hz, C═CH, thiophene ring), 7.05 d (1H, J = 7.5 Hz, 127.90, 127.90, 128.99, 130.43, 131.48, 138.10, 141.33, C─CH, thiophene ring), 7.36 d (J = 1H,7.3 Hz, S─CH, thio- 156.36, 166.71. MS: m/z: 357.11 [M+H]+ . Found, %: C-53.92; phene ring), 7.80 t (1H, J = 7.3 Hz, HAr ), 7.86 s (1H, CH═C), H-3.39; N-15.72. C16 H12 N4 O2 S2 . Calcd., %: C-53.89; H-3.41; 7.97 t (1H, J = 1.5 Hz, HAr ), 8.12 d (1H, J = 7.5 Hz, HAr ), N-15.74. 8.49 t (1H, J = 0.5 Hz, HAr ), 8.56 s (2H, CH─N─CH, triazole 5-(3-hydroxybenzylidene)−2-(thiophen-2-yl)−3-(4H-1,2, ring). 13 C NMR spectrum (125 MHz, DMSO-d6 ) δ 62.30, 4-triazol-4-yl)thiazolidin-4-one (5c): Yield 63%, m.p. 160– 122.39, 122.46, 123.15, 125.96, 127.27, 128.15, 129.45, 162 ◦ C. IR spectrum, ν, cm−1 : 693 (C─S), 1115 (─N─N─), 131.76, 132.46, 135.25, 137.85, 141.33, 148.46, 166.77. MS: 1544 (─C─N), 1609 (─C═N─), 1725 (C═O), 3021 (C─H), m/z: 386.04 [M+H]+ . Found, %: C-49.86; H-2.88; N-18.17. 3247 (C─OH). 1 H NMR spectrum (500 MHz, DMSO-d6 ), δ, C16 H11 N5 O3 S2 . Calcd., %: C-49.83; H-2.86; N-18.19. ppm: 6.29 d (1H, J = 0.6 Hz, CH, thiazolidinone ring), 6.80 d 5-(2-nitrobenzylidene)−2-(thiophen-2-yl)−3-(4H-1,2,4- (1H, J = 7.3 Hz, HAr ), 6.93 q (1H, J = 1.1 Hz, HAr ), 6.96–7.02 m triazol-4-yl)thiazolidin-4-one (5g): Yield 66%, m.p. 164– (1H, HAr ), 7.05 d (1H, J = 1.7 Hz, C─CH, thiophene ring), 166 ◦ C. IR spectrum, ν, cm−1 : 729 (C─S), 1161 (─N─N─), 7.20 t (1H, J = 1.6 Hz, HAr ), 7.24 t (1H, J = 7.4 Hz, HAr ), 1365 (C─NO2 ), 1522 (─C─N), 1638 (─C═N─), 1746 (C═O), 7.36 d (1H, J = 1.7 Hz, S─CH, thiophene ring), 7.77 s (1H, 3026 (C─H). 1 H NMR spectrum (500 MHz, DMSO), δ, 6.29 d CH═C), 8.55 s (2H, CH─N─CH, triazole ring), 9.16 s (1H, (1H, J = 0.6 Hz, CH, thiazolidinone ring), 7.00 t (1H, J = 7.3 Hz, Ar─OH). 13 C NMR spectrum (125 MHz, DMSO-d6 ) δ, ppm: C═CH, thiophene ring), 7.05 d (1H, J = 7.5 Hz, C─CH, thio- 62.30, 116.54, 117.00, 122.83, 125.13, 126.06, 127.27, 12.90, phene ring), 7.36 d (1H, J = 7.3 Hz, S─CH, thiophene ring), 129.75, 132.17, 135.30, 138.10, 141.33, 157.41, 166.72. 7.64 d (1H, J = 1.6 Hz, HAr ), 7.71 d (1H, J = 1.5 Hz, HAr ), 7.80 MS: m/z: 357.15 [M+H]+ . Found: C-53.92; H-3.39; N-15.72. d (1H, J = 7.4 Hz, HAr ), 8.01–8.08 m (2H, HAr ), 8.55 s (2H, C16 H12 N4 O2 S2 . Calcd., %: C-53.95; H-3.40; N-15.75. CH─N─CH, triazole ring). 13 C NMR spectrum (125 MHz, 5-(4-hydroxybenzylidene)−2-(thiophen-2-yl)−3-(4H-1,2, DMSO-d6 ) δ 62.30,123.76, 125.31, 125.96, 126.39, 127.27, 4-triazol-4-yl)thiazolidin-4-one (5d): Yield 71%, m.p. 168– 128.15, 129.69, 129.80, 130.64, 131.59, 137.85, 141.33, 170 ◦ C. IR spectrum, ν, cm−1 : 697 (C─S), 1110 (─N─N─), 148.25, 166.63. MS: m/z: 386.05 [M+H]+ . Found, %: C-49.86; 1540 (─C─N), 1601 (─C═N─), 1740 (C═O), 3024 (C─H), H-2.88; N-18.17.C16 H11 N5O3 S2 . Calcd., %: C-49.84; H-2.87; 3242 (C─OH). 1 H NMR spectrum (500 MHz, DMSO-d6 ), δ, N-18.15. ppm: 6.29 d (1H, J = 0.6 Hz, CH, thiazolidinone ring), 6.89- 5-(4-fluorobenzylidene)−2-(thiophen-2-yl)−3-(4H-1,2,4- 6.95 m (2H, HAr ), 7.00 t (1H, J = 7.5 Hz, C═CH, thiophene triazol-4-yl)thiazolidin-4-one (5h): Yield 72%, m.p. 136– ring), 7.05 d (1H, J = 7.5 Hz, C─CH, thiophene ring), 7.36 d 138 ◦ C. IR spectrum, ν, cm−1 : 758 (C─S), 1111 (─N─N─), (1H, J = 7.3 Hz, S─CH, thiophene ring), 7.44–7.50 m (2H, HAr ), 1213 (C─F), 1592 (─C─N), 1629 (─C═N─), 1742 (C═O), 3023 7.77 s (1H, CH═C), 8.55 s (2H, CH─N─CH, triazole ring), 9.53 (C─H). 1 H NMR spectrum (500 MHz, DMSO-d6 ), δ, 6.29 d (1H, s (1H, Ar─OH). 13 C NMR spectrum (125 MHz, DMSO-d6 ) δ J = 0.6 Hz, CH, thiazolidinone ring), 7.00 t (1H, J = 7.3 Hz, 62.30, 116.33, 122.14, 126.06, 127.27, 127.87,127.90, 131.65, C═CH, thiophene ring), 7.05 d (1H, J = 7.5 Hz, C─CH, thio- 131.78, 138.10, 141.33, 159.39, 166.74. MS: m/z: 357.09 phene ring), 7.19–7.27 m (2H, HAr ), 7.36 d (J = 1H, 1.7 Hz, [M+H]+ . Found, %: C-53.92; H-3.39; N-15.72. C16 H12 N4 O2 S2 . S─CH, thiophene ring), 7.62–7.69 m (2H, HAr ), 7.78 s (1H, Calcd., %: C-53.94; H-3.42; N-15.71. CH═C), 8.55 s (2H, CH─N─CH, triazole ring). 13 C NMR spec- 5-(4-nitrobenzylidene)−2-(thiophen-2-yl)−3-(4H-1,2,4- trum (125 MHz, DMSO-d6 ) δ 62.30, 116.14, 116.30, 122.14, triazol-4-yl)thiazolidin-4-one (5e): Yield 68%, m.p. 174– 126.06, 127.27, 127.90, 130.23, 130.25, 130.31, 130.37, 176 ◦ C. IR spectrum, ν, cm−1 : 725 (C─S), 1166 (─N─N─), 127.90, 130.23, 130.25, 130.31, 130.37, 131.61, 138.10, 1369 (C─NO2 ), 1520 (─C─N), 1631 (─C═N─), 1741 (C═O), 141.33, 160.44, 162.46, 166.81. MS: m/z: 360.05 [M+2H]+ . 3023 (C─H).1 H NMR spectrum (500 MHz, DMSO-d6 ), δ, ppm: Found, %: C-53.62; H-3.09; N-15.63. C16 H11 FN4 OS2 . Calcd., 6.29 d (1H, J = 0.6 Hz, CH, thiazolidinone ring). 7.00 t (1H, %: C-53.65; H-3.08; N-15.62. J = 7.4 Hz, C═CH, thiophene ring), 7.05 d (1H, J = 7.5 Hz, 5-(4-chlorobenzylidene)−2-(thiophen-2-yl)−3-(4H-1,2,4- C─CH, thiophene ring), 7.36 d (1H, J = 7.3 Hz, S─CH, triazol-4-yl)thiazolidin-4-one (5i): Yield 69%, m.p. 184– thiophene ring), 7.84 s (1H, CH═C), 7.91–7.97 m (2H, HAr ), 186 ◦ C. IR spectrum, ν, cm−1 : 667 (C─S), 781 (C─Cl), 1075
25728288, 2024, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300116 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 136 GODHANI ET AL. (─N─N─), 1558 (─C─N), 1614 (─C═N─), 1734 (C═O), 3014 5-(4-bromobenzylidene)−2-(thiophen-2-yl)−3-(4H-1,2, (C─H). 1 H NMR spectrum (500 MHz, DMSO-d6 ), δ, 6.29 d (1H, 4-triazol-4-yl)thiazolidin-4-one (5m): Yield 67%, m.p. 160– J = 0.6 Hz, CH, thiazolidinone ring), 7.00 t (1H, J = 7.3 Hz, 162 ◦ C. IR spectrum, ν, cm−1 : 721 (C─Br), 781 (C─S),1054 C═CH, thiophene ring), 7.03–7.07 m (1H, CH═C, thiophene (─N─N─), 1495 (─C─N), 1608 (─C═N─), 1737 (C═O), ring), 7.31–7.39 m (3H, HAr ), 7.48–7.54 m (2H, HAr ), 7.78 s 3075 (C─H). 1 H NMR spectrum (500 MHz, DMSO-d6 ), δ, (1H, CH═C), δ 8.55 s (2H, CH─N─CH, triazole ring). 13 C NMR 6.29 d (1H, J = 0.6 Hz, CH, thiazolidinone ring), 7.00 t (1H, spectrum (125 MHz, DMSO-d6 ) δ 62.30, 122.14, 126.06, J = 7.3 Hz, C═CH, thiophene ring), 7.06 d (1H, J = 1.6 Hz, 127.27, 127.90, 129.28, 130.07, 131.27, 131.46, 133.92, C─CH, thiophene ring), 7.36 d (1H, J = 1.7 Hz, S─CH, 137.85, 141.33, 166.79. MS: m/z: 376.03 [M+2H]+ . Found, %: thiophene ring), 7.53–7.60 m (4H, HAr ), 7.76 s (1H, CH═C), C-51.27; H-2.96; N-14.95. C16 H11 ClN4 OS2 . Calcd., %: C-51.28; 8.55 s (2H, CH─N─CH, triazole ring). 13 C NMR spectrum H-2.97; N-14.97. (125 MHz, DMSO-d6 ) δ 62.62, 122.17, 123.44, 125.98, 127.26, 5-(3-chlorobenzylidene)−2-(thiophen-2-yl)−3-(4H-1,2,4- 128.31, 130.29, 131.61, 131.81, 132.20, 138.04, 141.33, triazol-4-yl)thiazolidin-4-one (5j): Yield 62%, m.p. 171– 166.78. MS: m/z: 421.04 [M+2H]+ . Found, %: C-45.83; H- 173 ◦ C. IR spectrum, ν, cm−1 : 669 (C─S), 785 (C─Cl), 1072 2.64; N-13.36. C16 H11 BrN4 OS2 . Calcd., %: C-45.81; H-2.66; (─N─N─), 1559 (─C─N), 1617 (─C═N─), 1731 (C═O), N-13.37. 3018 (C─H). 1 H NMR spectrum (500 MHz, DMSO-d6 ), δ, 5-(3-methoxybenzylidene)−2-(thiophen-2-yl)−3-(4H-1, 6.29 d (1H, J = 0.6 Hz, CH, thiazolidinone ring), 7.00 t (1H, 2,4-triazol-4-yl)thiazolidin-4-one (5n): Yield 61%, m.p. 154– J = 7.3 Hz, C═CH, thiophene ring), 7.03–7.07 m (1H, CH═C, 156 ◦ C. IR spectrum, ν, cm−1 : 627 (C─S), 1025 (─N─N─), thiophene ring), 7.36 d (1H, J = 1.7 Hz, S─CH, thiophene 1467 (─C─N), 1645 (─C═N─), 1739 (C═O), 2917 (C─OCH3 ), ring), 7.41 d (1H, J = 5.5 Hz, HAr ), 7.44–7.52 m (3H, HAr ), 3073 (C─H). 1 H NMR spectrum (500 MHz, DMSO-d6 ), δ, 3.82 7.78 s (1H, CH═C), 8.56 s (2H, CH─N─CH, triazole ring). 13 C s (3H, Ar─OCH3 ), 6.29 d (1H, J = 0.6 Hz, CH, thiazolidinone NMR spectrum (125 MHz, DMSO-d6 ) δ 62.30, 122.42, 126.06, ring), 6.95 d (1H, J = 7.5 Hz, HAr ), 7.00 t (1H, J = 7.3 Hz, 127.27, 127.90, 128.49, 129.27, 130.77, 132.30, 134.77, 135, C═CH, thiophene ring), 7.02–7.07 m (1H, CH═C, thiophene 137.85, 141.33, 166.77. MS: m/z: 376.15 [M+2H]+ . Found, %: ring), 7.09–7.13 m (1H, HAr ), 7.27 d (1H, J = 7.5 Hz, HAr ), C-51.27; H-2.96; N-14.95. C16 H11 ClN4 OS2 . Calcd., %: C-51.28; 7.34–7.41 m (2H, S─CH, thiophene ring), 7.76 s (1H, C═CH), H-2.98; N-14.97. 8.56 s (2H, CH─N─CH, triazole ring). 13 C NMR spectrum 5-(2-chlorobenzylidene)−2-(thiophen-2-yl)−3-(4H-1,2,4- (125 MHz, DMSO-d6 ) δ 55.30, 62.30, 113.74, 115, 122.80, triazol-4-yl)thiazolidin-4-one (5k): Yield 65%, m.p. 175– 125.89, 126.06, 127.27, 127.90, 129.23, 132.25, 134.97, 177 ◦ C. IR spectrum, ν, cm−1 : 672 (C─S), 788 (C─Cl), 1077 137.85, 141.33, 159.88, 166.79. MS: m/z: 371.07 [M+H]+ . (─N─N─), 1564 (─C─N), 1611 (─C═N─), 1733 (C═O), 3015 Found, %: C-55.12; H-3.81; N-15.12. C17 H14 N4 O2 S2 . Calcd., (C─H). 1 H NMR spectrum (500 MHz, DMSO-d6 ), δ, 6.28 %: C-55.16; H-3.82; N-15.14. d (1H, J = 0.6 Hz, CH, thiazolidinone ring), 6.97–7.07 m 5-(4-methoxybenzylidene)−2-(thiophen-2-yl)−3-(4H-1, (2H, C═CH─CH, thiophene ring), 7.30–7.44 m (4H, HAr ), 2,4-triazol-4-yl)thiazolidin-4-one (5o): Yield 73%, m.p. 7.50 d (1H, J = 7.0 Hz, HAr ), 7.93 s (1H, CH═C), 8.55 s (2H, 165–167 ◦ C. IR spectrum, ν, cm−1 : 631 (C─S), 1028 CH─N─CH, triazole ring). 13 C NMR spectrum (125 MHz, (─N─N─),1466 (─C─N), 1644 (─C═N─), 1738 (C═O), DMSO-d6 ) δ 62.30, 126.06, 126.58, 127.27, 127.90, 127.93, 2916 (C─OCH3 ), 3075 (C─H). 1 H NMR spectrum (500 MHz, 128.05, 129.19, 129.71, 132.86, 134.06, 134.28, 137.85, DMSO-d6 ), δ, 3.81 s (3H, Ar─OCH3 ), 6.29 d (1H, J = 0.6 Hz, 141.33, 166.59. MS: m/z: 376.08 [M+2H]+ . Found, %: C- CH, thiazolidinone ring), 6.97–7.07 m (4H, CH═C, thiophene 51.27; H-2.96; N-14.95. C16 H11 ClN4 OS2 . Calcd., %: C-51.24; ring), 7.36 d (1H, J = 1.7 Hz, S─CH, thiophene ring), 7.44– H-2.94; N-14.97. 7.50 m (2H, HAr ), 7.76 s (1H, C═CH), 8.56 s (2H, CH─N─CH, 5-(4-methylbenzylidene)−2-(thiophen-2-yl)−3-(4H-1,2, triazole ring). 13 C NMR spectrum (125 MHz, DMSO-d6 ) 4-triazol-4-yl)thiazolidin-4-one (5l): Yield 74%, m.p. 142– δ 55.33, 62.30, 114.97, 122.14, 126.06, 127.27, 127.90, 144 ◦ C. IR spectrum, ν, cm−1 : 666 (C─S), 1074 (─N─N─), 128.81, 131.58, 132.21, 137.85, 141.33, 160.54, 166.81. MS: 1460 (─C─N), 1628 (─C═N─), 1735 (C═O), 2950 (C─CH3 ), m/z: 371.15 [M+H]+ . Found, %: C-55.12; H-3.81; N-15.12. 3017 (C─H). 1 H NMR spectrum (500 MHz, DMSO-d6 ), δ, C17 H14 N4 O2 S2 . Calcd., %: C-55.17; H-3.83; N-15.13. 2.41 d (3H, J = 0.6 Hz, Ar-CH3 ), 6.28 d (1H, J = 0.6 Hz, CH, thiazolidinone ring), 6.99 t (1H, J = 7.3 Hz, C═CH, thio- phene ring), 7.05 d (1H, J = 1.6 Hz, C─CH, thiophene ring), 3 RESULTS AND DISCUSSION 7.32 d (2H, J = 7.5 Hz, HAr ), 7.36 d (1H, J = 1.7 Hz, S─CH, thiophene ring), 7.44–7.50 m (2H, HAr ), 7.76 s (1H, CH═C), The required compounds were made using a three-step 8.55 s (2H, CH─N─CH, triazole ring). 13 C NMR spectrum process. Thiophene-2-carbaldehyde (1) and 1,2,4-triazol-4- (125 MHz, DMSO-d6 ) δ 21.36, 62.30, 122.14, 126.06, 127.27, amine (2) were reacted in ethanol using acetic acid as a 127.90, 128.71, 129.53, 131.27, 131.52, 138.10, 139.32, catalyst to produce imines (3) in the first step. Thiogly- 141.33, 166.74.MS: m/z: 355.07 [M+H]+ . Found, %: C-57.61; colic acid was then used to cyclize it into 4-thiazolidinone H-3.98; N-15.81. C17 H14 N4 OS2 . Calcd., %: C-57.63; H-3.96; (4). In the last step, arylidene substituents (5a–o) contain- N-15.80. ing various electron-donating and electron-withdrawing
25728288, 2024, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300116 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License GODHANI ET AL. 137 TA B L E 1 In vitro antimicrobial activities of all products expressed as MIC [μg mL−1 ] (5a–o). Minimum inhibition concentration Minimum inhibition concentration for bacteria (μg mL−1 ) for fungi (μg mL−1 ) Compounds e.c. s.m. s.e. s.p. a.n. f.j. 5a 1000 1400 1000 600 1500 2000 5b 1200 1000 800 1200 1000 1500 5c 1200 1400 800 1400 1000 1200 5d 2400 2400 2400 1200 1000 1200 5e 12.5 25 1200 25 2000 2500 5f 2400 1200 25 1200 1500 1500 5g 2400 2400 2400 1200 1200 1200 5h 2400 2400 2400 1200 1400 2000 5i 25 12.5 1000 50 200 1200 5j 2400 1000 12.5 1000 1200 1000 5k 1200 2000 1000 2000 600 2000 5l 1400 1200 25 25 1200 2000 5m 50 50 1000 1000 2000 2000 5n 1200 1200 1200 1000 1400 2500 5o 1200 1200 1200 1000 1200 2500 Chloramphenicol 10 10 10 10 – – Nystatin – – – – 200 800 Abbreviations: e.c., Escherichia coli (ATCC 25922); s.m., Serratia marcescens (ATCC 14756); s.e., Staphylococcus epidermis (ATCC 12228); s.p., Streptococcus pyogens (ATCC 19615); a.n., Aspergillus niger (ATCC 16404); f.j., Fusarium javanicum (ATCC 22403). groups were generated using an active methylene group of 25922), Serratia marcescens (gram-negative, ATCC 14756), 4-thiazolidinone. The IR spectra of compound (3) exhibit Staphylococcus epidermis (gram-positive, ATCC 12228), and the azomethene stretching development at 1618 cm−1 . The Streptococcus pyogens (gram-positive). Antifungal activity proton signal from the ─CH2 group was found at 3.76 ppm was screened against two fungal species, Aspergillus niger in the 1 H NMR spectra of the product (4). The existence (ATCC 16404) and Fusarium javanicum (ATCC 22403), where of various functional groups in the targeted compounds nystatin was used as the standard antifungal drug. Follow- was confirmed by the IR spectra of the compound (5a). ing the guidelines of the Clinical and Laboratory Standards The carbonyl group of the 4-thiazolidinone ring was con- Institute,23 the minimum inhibitory concentration (MIC) firmed at 1741 cm−1 . The ─C─S bond at 678 cm−1 was of each synthesized chemical was calculated using the used to confirm the existence of the thiophene ring, and broth microdilution technique (CLSI). The results of the the 1 H NMR signal at 7.76 ppm was used to confirm the antimicrobial evaluation showed that compound (5e) with presence of the ═C─H bond (arylidene proton). The hybrid MIC values of 12.5, 25, and 50 μg mL−1 was found to entity had aromatic protons in the range of 6.29–8.55 ppm. be prominent, good, and moderate to the standard drug Using a chemical shift at 166.8 ppm, the carbonyl carbon chloramphenicol against E. coli, S. marcescens, S. epidermis of thiazolidinone was determined. Moreover, the signal at bacterial strain respectively. Compound (5i) with MIC val- 131.62 ppm validated the thiazolidinone vinylic carbon. The ues of 25, 12.5, and 50 μg mL−1 was found to be good, presence of carbon atoms on the triazole ring was verified at prominent, and moderate to the standard drug chloram- 141.34 ppm. The mass of the produced molecule is shown phenicol against E. coli, S. marcescens, S. epidermis bacterial by the m/z value of the compound (5a) at 341.14. The strain respectively. Compound (5m) with an MIC value of claimed structure was validated using the spectroscopic 50 μg mL−1 was found to be moderate to the standard drug data described above. chloramphenicol against E. coli, and S. marcescens bacterial strains. Compound (5f) with an MIC value of 25 μg mL−1 was found to be good to the standard drug chlorampheni- 3.1 Antimicrobial activity col against the S. epidermis bacterial strain. Compound (5j) with an MIC value of 12.5 μg mL−1 was found to be Using chloramphenicol as the standard antibacterial drug, prominent to the standard drug chloramphenicol against the antimicrobial activity of newly synthesized compounds the S. epidermis bacterial strain. Chloramphenicol, a stan- (5a–o) was tested against a representative panel of dard drug, and the S. epidermis bacterial strain were both bacteria, including Escherichia coli (gram-negative, ATCC successfully treated with compound (5l), which had an
25728288, 2024, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300116 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 138 GODHANI ET AL. F I G U R E 1 Genesis of synthesized 4-thiazolidinone hybrids (5a–o) based on commercially available drug piprozolin. FIGURE 2 Structural presentation of the effect of various functional groups on antimicrobial activity. MIC value of 25 μg mL−1 . Compounds (5i) and (5j) were 3.2 Structure activity relationship study also found to be moderately active with MIC values of 200 and 1000 μg mL−1 to the standard drug nystatin The antimicrobial efficacy of a few new hybrids (5a–o) has against A. niger, and F. javanicum fungal pathogen. The been examined in this work. The results of in vitro antibac- effects of these examinations were notable in Table 1 (See terial activity showed encouraging findings, as shown, Figure 1). as shown in Figure 2. We have created compounds with
25728288, 2024, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202300116 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License GODHANI ET AL. 139 SCHEME 1 Reaction pathway of thiophene-substituted thiazolidinones. various electron-withdrawing and electron-donating phenicol against E. coli, S. marcescens, and S. epidermis. groups for evaluating their antibacterial efficacy. Antimi- Moreover, (5i) and (5j) substituents were well active to crobial screening of the synthesized hybrids revealed that nystatin against A. niger and F. javanicum respectively (see compounds containing electron-withdrawing groups Supporting Information). nitro(4-NO2 , 3-NO2 ), chloro(4-Cl, 3-Cl), bromo(4-Br) were found most active against gram-negative and ACKNOWLEDGMENTS gram-positive bacterial and fungal strains. The only The authors are thankful to the Department of Chemistry electron-donating group methyl (4-CH3 ) is active against and Maharaja Krishnakumarsinhji Bhavnagar University for gram-positive bacteria S. epidermis. Outcomes of the providing the necessary facilities to carry out this work. antimicrobial activity revealed that electron-withdrawing group in the fourth position and third position while the F U N D I N G I N F O R M AT I O N electron-donating group in the fourth position emerged No funding has been received from any source. as antimicrobial agents as described in Figure 2 (See Scheme 1). C O N F L I C T S O F I N T E R E S T S TAT E M E N T The authors declare no conflicts of interest. 4 CONCLUSION REFERENCES 1. F. Abedinifar, E. Rezaei, M. Biglar, B. Larijani, H. Hamedifar, S. Ansari, M. Mahdavi. Recent strategies in the synthesis of thiophene derivatives: By a multicomponent reaction, we have created an entirely Highlights from the 2012–2020 literature, Mol. Divers. 2021, 25, 2571. new group of antimicrobial substances in the latest study, 2. T. B. Nguyen. Recent advances in the synthesis of heterocycles via which contains a 4-thiazolidinone core structure com- reactions involving elemental sulfur, Adv. Synth. Catal. 2020, 362, prising thiophene and triazole. The primary procedure 3448. involved Schiff base formation, which was cyclized to ˘ 3. H. Muglu, H. Yakan, H. A. Shouaib. New 1, 3, 4-thiadiazoles based on thiophene-2-carboxylic acid: Synthesis, characterization, and antimi- formed 4-thiazolidinone hybrid. The condensation reac- crobial activities, J. Mol. Struct. 2020, 1203, 127470. tion of 4-thiazolidinone and substituted aldehydes to gives 4. N. Singla, G. Singh, R. Bhatia, A. Kumar, R. Kaur, S. Kaur. Design, synthe- a targeted compound (5a–o). The synthesized hybrids sis and antimicrobial evaluation of 1,3,4-Oxadiazole/1,2,4-Triazole- had ingrained various functional groups containing sub- substituted thiophenes, ChemistrySelect 2020, 5, 3835. stituents with electron-donating and electron-withdrawing 5. R. Shah, P. Verma. Therapeutic importance of synthetic thiophene, Chem. Cent. J. 2018, 12, 137. groups for increases antimicrobial activities. Results of the 6. A. Alsayari, A. B. Muhsinah, Y. I. Asiri, M. Y. Alfaifi, S. E. Elbehairi, F. Alatibi, in vitro analysis stated that compounds (5e) and (5i) were Y. N. Mabkhot. Synthesis of antimicrobial agents of tetra-substituted the most effective antibacterial alternative due to their thiophenes from ethyl 5-(2-bromoacetyl)-4-phenyl−2-(phenylamino) high activity compared to the standard drug chloram- thiophene-3-carboxylate, J. Heterocycl. Chem. 2020, 57, 2911.
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