Greener approach for the synthesis of Isoxazole Derivatives as dual antibacterial and antioxidant agents

Abstract

In this study, a series of 3,5-dimethyl-4-nitroisoxazole derivatives (3a–3n) were synthesized and their antibacterial, antioxidant, and molecular docking profiles were evaluated to explore their potential as therapeutic agents. The compounds were synthesized efficiently using microwave-assisted reactions with ethanol as the solvent and piperidine as the base. The characterization of the synthesized compounds was achieved through various spectroscopic methods including ¹H NMR, ¹³C NMR, and HRMS techniques, providing detailed structural insights. The antibacterial screening (agar diffusion) showed that compound 3m exhibited the highest inhibition zones (18 mm against S. aureus, 15 mm against K. pneumoniae) comparable to tetracycline, followed by 3a (15 mm and 17 mm) and 3g (14 mm and 13 mm). The minimum inhibitory concentration (MIC) assays confirmed that 3m is the most potent (3.125 µg/mL against S. aureus and 6.25 µg/mL against K. pneumoniae), while 3g and 3a showed MICs of 6.25–12.5 µg/mL. The antioxidant activity (DPPH assay) revealed that moderate radical scavenging for 3k (IC₅₀ = 371.9 µg/mL) and 3m (IC₅₀ = 388.9 µg/mL), whereas most derivatives were weak or inactive. Furthermore, the molecular docking studies supported antibacterial and antioxidant activity through stable binding with bacterial (S. aureus) and peroxidase enzymes. Additionally, the ADME predictions indicated high oral absorption (>90 %), no Lipinski’s rule violations, moderate metabolic stability (1–2 reactions), and safe BBB permeability (−1.865 to −0.621 nm s⁻¹).