Synthesis, Biological Evaluation and Molecular Docking studies of Novel 3-aryl-5-(alkyl-thio)-1H-1,2,4-triazoles Derivatives targeting Mycobacterium tuberculosis

Abstract

A small library of new 3-aryl-5-(alkyl-thio)-1H-1,2,4-triazoles was synthesized and screened for the anti-mycobacterial potency against M. tuberculosis H₃₇Ra strain and M. bovis BCG both in active and dormant stage. Among the synthesized library, 25 compounds exhibited promising anti-TB activity in the range of IC₅₀0.03–5.88 μg/mL for dormant stage and 20 compounds in the range of 0.03–6.96 μg/mL for active stage. Their lower toxicity (>100 μg/mL) and higher selectivity (SI = >10) against all cancer cell lines screened makes them interesting compounds with potential anti-mycobacterial effects. Furthermore, to rationalize the observed biological activity data and to establish a structural basis of inhibition of mycobacterium tuberculosis, the molecular docking study was carried out against a potential target MTB CYP121 which revealed a significant correlation between the binding score and biological activity for these compounds. Cytotoxicity and in vivo pharmacokinetic studies suggested that 1,2,4-triazole analogs have an acceptable safety index, in vivo stability and bio-availability.

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A small library of new 3-aryl-5-(alkyl-thio)-1H-1,2,4-triazoles was synthesized and screened for the anti-mycobacterial potency against H37Ra strain, M. bovis BCG both in active and dormant stage. Among the synthesized library, 25 compounds exhibited promising anti-TB activity in the range of IC50 0.03–5.88 µg/mL for dormant stage and 20 compounds in the range of 0.03–6.96 µg/mL for active stage. These compounds were shown to have more specificity towards mycobacteria than other Gram-negative and Gram-positive pathogenic bacteria.

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