Synthesis of Novel Triazolethione-, Thiadiazole-, and Triazole-Functionalized Quinazolin-4(3H)-one Derivatives and Their Antimicrobial Activity and Docking Studies

A series of novel triazolethione-, thiadiazole-, and triazole-functionalized quinazolin-4(3H)-one derivatives have been synthesized from 2-amino-6-(trifluoromethyl)benzonitrile (1). The acid hydrolysis of 1 gave 2-amino-6-(trifluoromethyl)benzoic acid (2) which was cyclized with trifluoroacetamide to obtain 2,5-bis(trifluoromethyl)quinazolin-4(3H)-one (3). Compound 3 was alkylated with ethyl 2-bromoacetate, and treatment of the resulting ethyl 2-[4-oxo-2,5-bis(trifluoromethyl)-3,4-dihydroquinazolin-3-yl]acetate (4) with hydrazine hydrate produced the corresponding acetohydrazide 5. The latter reacted with substituted phenyl isothiocyanates to afford thiourea derivatives 6 which were converted to triazolethione-, thiadiazole-, and triazole-functionalized quinazolin-4(3H)-one derivatives 7a-7d, 8a-8d, and 9a-9d via reactions with sodium hydroxide, sulfuric acid, and hydrazine hydrate, respectively. The synthesized compounds were screened against Gram-positive and Gram-negative bacteria and fungal strains. Compounds 7b, 7d, and 9b showed high activity against Bacillus subtilis MTCC 121 at a concentration of lower than 8.0 mu M. These compounds were also screened for biofilm inhibition activity against B. subtilis MTCC 121 using erythromycin as standard and were subjected to molecular docking studies toward human NAD[P]H-quinone oxidoreductase.