Microwave-assisted green synthesis of novel benzoxazole/benzothiazole-pyrazole hybrids with potential anti-inflammatory, anti-tubercular, and antimicrobial properties.

We report the efficient microwave-assisted synthesis of novel benzoxazole/benzothiazole derivatives using lemon juice as a natural catalyst in aqueous medium, aligning with green chemistry principles. This eco-friendly method offers a rapid and sustainable alternative for heterocycle construction. The synthesized compounds were structurally confirmed by IR, 1H NMR, 13C NMR, and HRMS techniques. The biological evaluation revealed promising anti-inflammatory, anti-tubercular, and antimicrobial activities. Notably, compounds 6i and 6j exhibited potent COX-2 inhibitory activity, with IC50 values of 81.21 ± 2.54 and 80.56 ± 2.98 μg/mL, respectively. Whereas compound 6e demonstrated anti-tubercular activity comparable to pyrazinamide, while others showed moderate efficacy. Furthermore, all synthesized derivatives exhibited notable antimicrobial activity comparable to standard drugs. To support the experimental anti-inflammatory findings, molecular docking studies against COX-2 (PDB ID: 5KIR) revealed strong binding affinities, which were further validated by molecular dynamics (MD) simulations and MM-GBSA binding free energy calculations, confirming complex stability and favorable interactions at the active site. Additionally, in silico ADME predictions indicated good drug-likeness, absorption, and pharmacokinetic profiles. These findings not only validate the therapeutic relevance of benzazole and benzothiazole scaffolds but also open new avenues for the development of green, bioactive molecules. Future studies will focus on structural optimization, in vivo evaluation, and mechanistic investigations to further explore their potential in pharmaceutical development.