Design, Synthesis, and Antimicrobial Study of Triad Hybrids of 1,2,3-Triazolo[4,5-b]pyridine: Click Chemistry and Azidation Using Hydrazine Hydrate

Abstract

Objective: The design and synthesis of new chemical entities (NCEs) with suitable physicochemical properties are crucial objectives in medicinal chemistry. This study focuses on the development of novel compounds with potential antimicrobial activity, employing a multi-step “click chemistry” strategy to synthesize ten diverse scaffolds derived from 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol. These compounds were designed to incorporate three distinct heterocyclic units within a single molecular framework. Methods: A novel azidation reagent—hydrazine hydrate in acetic acid—was employed for the efficient and environmentally benign synthesis of aryl azides. The resulting conjugates, 3-((1-(substituted phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3H-[1,2,3]triazolo[4,5-b]pyridines, were evaluated for antimicrobial activity against various microbial strains using minimum inhibitory concentration (MIC) assays. Additionally, molecular docking studies were conducted to assess the binding affinities of the synthesized compounds toward DNA gyrase (PDB ID: 4DUH). Results and Discussion: The synthesized conjugates exhibited varying degrees of antibacterial and antifungal activity in vitro. Among them, the scaffold bearing a trifluoromethyl (–CF₃) substituent on the aryl ring demonstrated the most potent antibacterial activity, with MIC values of 3.125 µg/mL against Bacillus subtilis and 6.75 µg/mL against Escherichia coli. In molecular docking simulations, the compound 3-((1-(2-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3H-[1,2,3]triazolo[4,5-b]pyridine showed favorable binding energy (−7.6 kcal/mol), comparable to that of streptomycin (−7.5 kcal/mol), penicillin (−6.6 kcal/mol), and amphotericin B (−9.7 kcal/mol). Conclusions: The newly synthesized conjugates exhibit promising antibacterial and antifungal properties. In particular, the compound 3-((1-(2-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-3H-[1,2,3]triazolo[4,5-b]pyridine demonstrates potent antimicrobial activity and favorable binding interactions with DNA gyrase, suggesting its potential as a novel antimicrobial agent.