Antibacterial Activity and Cytotoxicity Evaluation of 5-Amino-4-cyano-1,3-oxazole Derivatives: Synthesis, In Silico, and In Vitro Studies.

Bacterial infections contribute to many human diseases and cancer development, and their increasing incidence, together with rising antimicrobial resistance, underscores the urgent need for new potent biologically active compounds. Quantitative structure-activity relationship (QSAR) modeling was conducted to evaluate a series of oxazole derivatives as antibacterials. Eighteen new 5-amino-4-cyano-1,3-oxazoles with promising predictive properties were synthesized and reliably characterized. Fourteen compounds were found to inhibit bacterial growth (MICs varied from 8 to 512 µg/mL). Eight derivatives exhibited the highest activity against colistin-resistant Escherichia coli and Staphylococcus aureus isolates with MICs of 8-64 µg/mL. Moreover, six compounds exhibited activities greater or similar to that of reference oxacillin and cefepime against clinical isolates. Analysis of the studied 5-amino-4-cyano-1,3-oxazoles as target-directed glutathione S-transferase (GST) inhibitors showed that derivatives 7, 11, and 12 inhibited GSTA1-1 with an IC50 range of 3.2-7.5 µM. Molecular docking results indicate that these compounds can occupy the enzyme's active site. The cytotoxicity results in L20B and RD cell lines showed that compounds 11 and 12 demonstrated significant cytostatic effects, with CD50 values ranging from 0.02 to 2 µg/mL. Additionally, these two compounds showed moderate acute toxicity toward D. magna, with LC50 values of 7.27 ± 1.22 and 5.10 ± 1.07 mg/L (D.R. Passino classification).