Design, synthesis, in vitro anticancer and antimicrobial evaluation, SAR analysis, molecular docking and dynamic simulation of new pyrazoles, triazoles and pyridazines based isoxazole

•A series of pyrazoles, triazoles and pyridazines derivatives bearing isoxazole were synthesized.•Antimicrobial and cytotoxic effects were evaluated.•All synthesized compounds were found to broad spectrum antimicrobial activity.•Compounds 5a, 6a and 6b were the most effective against HepG2 and MCF-7.•Promising analogues 5a,6a and 6b were selected for molecular docking and dynamic simulation. A new series of pyrazoles, triazoles and pyridazines based isoxazole were synthesized, and well characterized. Their antibacterial, antifungal and cytotoxic activities were successfully evaluated. Result showed that compound 6a followed by 5a and 6b exhibited promising antimicrobial activity against all strains, often higher than the standard drugs, with MIC values ranging respectively from 3.25 to 38.29 µM, 4.86–114.32 and 17.96–145.06 while the rest of the compounds were found to be moderately active. Cytotoxicity investigation against breast adenocarcinoma (MCF-7) and hepatocellular carcinoma (HepG2) cell lines showed that 6a (IC50 = 6.76 µM and 5.77 µM) exhibited excellent activity followed by 5a (IC50 = 8.2 µM and 7.24 µM) and 5b (IC50 = 12.26 µM and 13.7 µM), respectively. Structure activity relationship (SAR) revealed that pyridazinone scaffolds containing amino and cyano groups, as well as aryl have the best activity. Molecular docking studies on the intriguing candidate compounds were performed with microbial and cancer targets, revealing that compounds 5a and 6b were associated with significant docking scores. Furthermore, the dynamic nature, binding interaction, and protein–ligand stability were explored through molecular dynamics (MD) simulation study. Various analyzing parameters (RMSD and RMSF) from the MD simulation trajectory have suggested stability of the compound during the 100 ns MD simulation study. Hopefully in future, the present research highlighted the potential of derivatives with pyridazinone as well as those with 1,2,3-triazole scaffolds bearing isoxazole as a lead compound for designing dual antimicrobial and anticancer agents. Graphical abstract [Display omitted] .