Rational design of new thienopyridine heterocycles tethering thiophene moiety as antimicrobial agents: Synthesis and computational biology study

In this study, we report the rational design, synthesis, and computational evaluation of novel thienopyridine-based heterocycles incorporating a thiophene moiety as potential antimicrobial agents. Five thienopyridine derivatives were successfully synthesized and thoroughly characterized using spectroscopic techniques, including nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). The in vitro antimicrobial activities of the synthesized compounds were evaluated against a panel of Gram-positive and Gram-negative bacterial strains, as well as fungal pathogens. Most compounds exhibited moderate to strong inhibitory effects, with compounds 10 and 11 showing the highest antibacterial activity, while derivatives 8 and 11 demonstrated the most potent antifungal effects. The introduction of bulky aromatic substituents, such as biphenyl and naphthalene, enhanced both antibacterial and antifungal properties, likely due to increased aromaticity and stronger π–π interactions with microbial targets. Additionally, the presence of a cyano (CN) group notably improved antifungal activity. Molecular dynamics simulations indicated that compound 8 formed stable interactions with key residues at the binding site, maintaining complex stability throughout the simulation period. Predictions of drug-likeness and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties revealed a favorable pharmacological profile, supporting its potential as a promising lead compound for the development of potent and low-toxicity antimicrobial agents.