New Isoxazole Derivatives: Design, Synthesis, Crystal Structure, Antimicrobial Assessments, and In Silico Studies

The synthesis of new isoxazole derivatives is described, and their antimicrobial potential is evaluated through in vitro and in silico approaches. Structural elucidation is achieved by FT-IR, NMR (1H, 13C), MS, and XRD analyses. Biological studies show significant inhibitory activity, particularly for compound 4e against C. albicans. Docking and molecular dynamics confirm strong receptor binding and favorable ADMET profiles.

Abstract

The present work reports the synthesis of new isoxazole derivatives as well as assessments of their antimicrobial activity through both in vitro and in silico approaches. The structures of all new compounds were determined by spectroscopic methods, including FT-IR and NMR (¹H, ¹³C), and unambiguously confirmed by mass spectrometry (MS) and single-crystal X-ray diffraction (XRD). The new isoxazoles were tested in vitro for their antimicrobial activity and the results indicate that they exhibit significant inhibitory activity against the tested microbial strains compared to the reference antibiotics. Notably, 4e, 4g, and 4h exhibited significantly higher activity against Candida albicans compared to their activity against Escherichia coli and Bacillus subtilis. Minimum inhibitory concentration (MIC) measurements showed that the compounds were effective against C. albicans, B. subtilis, and E. coli, with MIC values ranging from 6 to 60 µg/mL, 10 to 80 µg/mL, and 30 to 80 µg/mL, respectively. Furthermore, molecular docking studies performed on the isoxazoles revealed significant affinities for the three target receptors (1KZN, 1OF0, and 1EAG) compared to standard antibiotics. The molecular dynamics simulation analysis of the 1KZN-4e, 1OF0-4e, and 1EAG-4e complexes revealed a high degree of stability between the ligand 4e and the target proteins. In addition, in silico predictions indicate that the isoxazole compounds were analyzed on the basis of their similarity to existing drugs and their ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties. These analyses show favorable pharmacokinetic profiles with no evidence of toxicity.

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