Synthesis, In vitro Antibacterial and Antimycobacterial Activity and Docking Study of Thieno(3,2-e)(1,2,4)triazolo(1,5-c)pyrimidines

Background: Emergence of drug resistance and severe side effects with current antitubercular drugs urges the development of more efficacious and safer new agents. The present study focused on this direction to develop new hetero-fused pyrimidines as potential antitubercular agents. Objective: The objective of the study was to synthesize and assess the antibacterial and antimycobacterial activity of novel 1,2,4-triazole ring bearing hetero-fused thienopyrimidines (6a-j & 7a-j). Also to evaluate the binding pattern of synthesized molecules at the target site and study their ADME properties by in silico tools. Methods: Two series of hetero fused thienopyrimidines (6a-j & 7a-j) were synthesized and tested for their antibacterial potentiality against B. subtilis, S. aureus, E. coli, and K. pneumonia. Compounds with potential antibacterial activity were further tested for their antitubercular activity against Mycobacterium tuberculosis (MTB) H37Rv and an isoniazid (INH)-resistant clinical sample of MTB using broth microdilution method. The binding efficacy at the enzyme site was evaluated by the molecular docking study using pantothenate synthetase (MTB-PS) (PDB: 3IVX) as the target protein. Further, in silico ADME properties of title compounds were explored by Swiss ADME online tools. Results: In this study, few compounds were found promising in exhibiting potent inhibitory activity against E. coli and MTB. Among these compounds, 6h (MTB: MIC-17.13±0.88 μM) and 6i (MTB: MIC-17.55±0.72 μM) displayed significant antimycobacterial activity. The molecular docking results suggested the efficient binding of biologically potential molecules. Conclusion: Compounds bearing N-benzyl moiety at the core nucleus with a p-nitro aryl side chain (6h) exhibited significant antitubercular activity. In silico studies showed effective binding at the target site and also indicated good compatibility in ADME properties.