Synthesis of New [1,2,4]Triazolo[3,4-b][1,3,4]thiadiazines and Study of Their Anti-Candidaland Cytotoxic Activities

Abstract

New triazolothiadiazine derivatives5a–hwere synthesized from 4-amino-3-(4-pyridyl)-5-mercapto-4H-1,2,4-triazole (3) with substituted aryl hydrazonoyl chlorides4a–h. The compounds were testedin vitroagainst elevenCandidaspecies and compared with standard drug ketoconazole. Among these compounds, the compounds bearingp-chlorophenyl5e,p-methoxyphenyl5c, phenyl5a,andp-sulphonamidophenyl5gsubstituents on triazolothiadiazine system were found to be the most effective derivatives againstCandidaspecies. Compound5ewas the most effective compound againstC. parapsilosis(ATCC 22019),C. albicans(ATCC 66027),C.specie [blood] 12810, andC.specie [urine] 300 with MIC value of 6.25 μg/mL, whereas ketoconazole exhibits the inhibitory activity with MIC value of 3–30 μg/mL against all tested strains. It was clear that there is a positive correlation between anti-Candidalactivity andp-chlorophenyl substitution on triazolothiadiazine ring. All the synthesized compounds were also investigated for their potential cytotoxicity on noncancer cell line (MCF-12) using WST-1 assay. Three compounds5d,5a,and5hwere found to have the same IC50value as that of standard drug ketoconazole against noncancer cell line MCF-12 (IC50≥ 1.0 × 105 μg/mL).