Discovery of novel thiophene amide derivatives with potent antibacterial activity

The escalating threat of Antibiotic resistance has become an urgent issue in global public health, and this study designed and synthesized 28 novel thiophene amide derivatives to address this challenge. In vitro Antibacterial activity tests showed that most of the derivatives exhibited broad-spectrum inhibitory activity against gram-negative and gram-positive bacteria, and Z10 was the most significant. The minimum inhibitory concentration (MIC) of compound Z10 against key strains was 1.40 to 2.33 μM, which was comparable to that of the positive control ciprofloxacin, and it showed low cytotoxicity to normal human liver cells (L02). Time-kill curve analysis confirmed its concentration-dependent bactericidal effect. Molecular docking simulations conducted using Schrodinger software show that the pyridine group of Z10 tightly binds to the carboxyl group, Lys-465 residue, and Leu-480 residue of the predicted MsbA protein target, thereby elucidating its Antibacterial mechanism. Theoretical prediction of ADME properties by ADMET lab 3.0 platform confirmed that all compounds met the pharmacokinetic criteria of potential drugs. Structure-activity relationship analysis showed that the Antibacterial activity was significantly enhanced when the R¹ substituent was ethyl and the R² substituent was an electron-donating heterocycle with small steric hindrance. In summary, thiophene amide derivatives (especially compound Z10) show broad prospects in the development of new Antibacterial drugs.

Antimicrobial; Drug design; Gram-negative bacteria; Synthesis.