Synthesis of some new 1-aryl-2-((3-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)thio) ethane-1-ones as antimicrobial agents

Abstract

A series of ten new 1-(aryl)-2-((3-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)thio)ethan-1-ones (4a-j) was synthesized by reacting 3-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-6-thiol (2) with substituted phenacyl bromides (3a-j) in the presence of N,N-diisopropylethylamine. These derivatives were comprehensively evaluated for their antimycobacterial, antibacterial, and antifungal activities. Among these, compound 4f demonstrated notable efficacy against mycobacterial, bacterial, and fungal strains, exhibiting performance comparable to standard drugs. Further, highly active compounds underwent detailed scrutiny of their binding interactions within the active site using the co-crystal structures of Mycobacterium tuberculosis (Protein Data Bank [PDB] ID 2x22) and glucosamine-6-phosphate synthase (PDB ID 2VF5), followed by rigorous molecular dynamics (MD) simulations. MD simulations were conducted for 300 ns to study the stability and behavior of both the ligand-protein complexes (2x22-4f and 2vf5-4f). The root mean square deviation values for complex 4f with proteins 2x22 and 2vf5 were found to be 3.2x3.5 Å and 2.6x2.8 Å, respectively, indicating the stability of the complexes.. KEYWORDS :Antibacterial, Antifungal, Antimycobacterial, Molecular Docking, Molecular Dynamics, Root mean square deviation.