Design, Synthesis and Antimicrobial Evaluation of Novel Pyridyl-Linked Triazolo[1,5-a]pyrimidine-6-Carboxamide Derivatives

Abstract

The increasing prevalence of antimicrobial resistance necessitates the development of new chemotherapeutic agents with improved efficacy and pharmacokinetic profiles. In the present study, a novel series of pyridyl-linked triazolo[1,5-a] pyrimidine-6-carboxamide derivatives (8a–8h) was rationally designed and synthesized through a multistep synthetic approach. The structures of the synthesized compounds were confirmed by melting point analysis, TLC, ¹H NMR, LC-MS, and elemental analysis. All compounds were evaluated for their in vitro antimicrobial activity against selected Gram-positive and Gram-negative bacterial strains as well as fungal pathogens using the cup plate diffusion method. Several derivatives exhibited moderate to good antimicrobial activity, with compounds 8d and 8g showing the most promising broad-spectrum effects. In silico ADME studies using SwissADME indicated favorable drug-likeness, high predicted gastrointestinal absorption, and full compliance with Lipinski’s rule-of-five. Furthermore, molecular docking studies against the bacterial target protein (PDB ID: 1KZN) revealed strong binding affinities and key interactions consistent with the observed biological activity. Collectively, these results suggest that pyridyl-linked triazolo[1,5-a]pyrimidine carboxamides represent a valuable scaffold for further optimization toward the development of novel antimicrobial agents.

Keywords
Triazolo[1,5-a]pyrimidine; Pyridyl derivatives; Antimicrobial activity; ADME prediction; Molecular docking; Drug-likeness