Design, Synthesis, In Vitro, and In Silico Evaluation of Isoxazole–Isoxazoline Conjugates as Potential Antimicrobial Agents

A new series of hybrid compounds (5a-h) incorporating both isoxazole and isoxazoline scaffolds has been successfully synthesized, characterized, and assessed for their antimicrobial propriety. The newly synthesized conjugates were characterized through various spectroscopic methods, including FT-IR, 1D and 2D NMR, along with mass spectrometry. The conjugate compounds were subsequently evaluated for their antimicrobial activity against the some pathogenic following bacterial strains. Compounds (5a-d) and (5h) demonstrated notable activity in vitro against Escherichia coli, exhibiting an inhibition zone diameter (IZD) of 16 ± 0.74 mm and an inhibition rate of 80%. This activity is comparable to that of ampicillin, which was selected as a standard for comparison. Compound (5c) exhibited notable efficacy against Bacillus subtilis, with an inhibition rate of 50%. Concurrently, compound (5a) was distinguished by its noteworthy antifungal properties, exhibiting an IZD of 21 ± 0.50 mm (77% inhibition), which is comparable to the standard reference amphotericin B. The minimal inhibitory concentration (MIC) tests indicated that the compound (5h) exhibited notable efficacy against E. coli, B. subtilis, and Candida albicans, with MICs of 10, 10, and 60 µg/mL, respectively, approaching the values of the established standards of amphotericin B and ampicillin. Molecular docking analysis revealed favorable binding affinities of compounds (5a-h) against E. coli, B. subtilis, and C. albicans, outperforming conventional antibiotics. Molecular dynamics simulations were carried out on (5h), the most effective antibacterial and antifungal compound. ADME-Tox evaluation showed high intestinal absorption, especially for (5d) and (5h) (100%), blood retention, and a favorable safety profile with efficient elimination.