SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF S-ACYL AND S/N-BISACYL DERIVATIVES OF 5-ARYL-2,4-DIHYDRO-1,2,4-TRIAZOLE-3-THIONES
Abstract
To obtain novel derivatives of 5-aryl-2,4-dihydro-1,2,4-triazole-3-thiones (1-3) (aryl = 2-, 3-, or 4-hydroxyphenyl) with potential biological activity, their reactions with isobutyl chloroformate were investigated. The reactions were carried out under mild conditions (acetone, K₂CO₃, 56°C, 5 h) using two different molar ratios (1:1 and 1:2) of triazolethiones (1-3) to isobutyl chloroformate. Analysis of the products by IR, №H NMR, and №іC NMR spectroscopy demonstrated that, at a 1:1 molar ratio, the reaction proceeded regioselectively to afford exclusively the S-acyl derivatives, namely O-isobutyl S-(5-(2-, 3-, or 4-hydroxyphenyl)-4H-1,2,4-triazol-3-yl) carbonothioates (4-6), in 65–80% yields. In contrast, increasing the molar ratio to 1:2 resulted in simultaneous acylation of both the sulfur atom and the NІ atom of the triazole ring, affording the corresponding S,N-bisacyl derivatives, namely isobutyl 3-(2-, 3-, or 4-hydroxyphenyl)-5-((isobutoxycarbonyl)thio)-1H-1,2,4-triazole-1-carboxylates (7–9), in yields of 70-91%. The antimicrobial activity of compounds 4-9 was evaluated by in vitro screening against Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and the fungi Candida albicans. The synthesized compounds exhibited noticeable antibacterial activity only against the Gram-positive strains, producing inhibition zones of 7-14 mm. In particular, the S,N-bisacyl derivatives (7-9) displayed significantly greater antibacterial activity (13-14 mm) than the corresponding S-acyl derivatives (4-6), which showed inhibition zones of only 7-8 mm. A regioselective method for the synthesis of S-acyl and S,N-bisacyl derivatives of 5-aryl-1,2,4-triazole-3-thiones has been developed. The S,N-bisacyl derivatives showed enhanced antibacterial activity against Gram-positive bacteria.
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