Methoxy and Thiophene Chalcone Derivatives Against Multidrug-resistant Bacteria: Synthesis, in Vitro Evaluation, and Molecular Docking Insights.

The global rise in antibiotic resistance demands the urgent development of new antibacterial agents. This study investigated the antibacterial potential of four synthesized methoxy and thiophene chalcone derivatives (designated 3a, 4a, 3b, and 4b) against clinically relevant bacterial pathogens. These compounds were prepared through Claisen-Schmidt condensation, while their chemical structures were verified through applying Fourier-transform infrared, mass spectrometry, 1H nuclear magnetic resonance (NMR), and 13C NMR. Their antibacterial activity was tested in vitro, employing minimum inhibitory concentration (MIC) and well diffusion assays. Among these synthesized compounds, 3a demonstrated the strongest antibacterial efficacy, showing notable inhibition zones and low MIC values against S. aureus and E. coli, suggesting an increased effectiveness against Gram-negative strains. Molecular docking studies targeting Penicillin-Binding Protein 4 from S. aureus indicated robust binding affinities, with 3a and 4a exhibiting interactions comparable to or even exceeding ampicillin. Additionally, computational Absorption, Distribution, Metabolism, Excretion, and Toxicity analysis confirmed promising pharmacokinetics, such as adherence with Lipinski's Rule of Five, high gastrointestinal absorption, and low toxicity profiles. These insights emphasize a great potential in the synthesized derivatives for further advancement in addressing multidrug-resistant bacterial infections, and potentially expanding the range of effective antibacterial drugs.