Experimental, spectroscopic, and theoretical investigation on structural and anticancer activities of Schiff bases derived from isonicotinohydrazide.

• Nine isoniazid hydrazones have been synthesized and fully characterized. • Crystal structure and Hirshfeld surface analysis of three derivatives namely INH4, INH8, and INH9. • DFT and TD-DFT were performed for analysis of geometry, vibrational and absorption spectra. • Molecular docking studies reveal a strong binding affinity with MDM2 (4HG7) protein. • In-vitro anticancer activity through MTT, AO/EtBr staining, ROS estimation, and mitochondrial membrane potential to investigate the mode of action. Isoniazid hydrazones are promising possibilities as medicines since they have preserved efficacy and are less toxic and resistant to resistance than parent Isoniazid (INH). Here, we have synthesized a series of Schiff bases (INH1–9) derived from a clinically approved antitubercular drug Isoniazid (INH). These synthesized ligands have been characterized by various spectroscopic techniques like IR, UV–vis., NMR, HRMS, etc. Moreover, single crystal of three derivatives viz. INH4, INH8, and INH9 has been determined and they crystallize in monoclinic crystal system. Hirshfeld surface analysis has been performed to ascertain intermolecular interactions present in these compounds. The molecular geometry optimization and vibrational analysis of these compounds were performed using density functional theory (DFT) studies utilizing B3LYP/6–31++ G (d, p) basis set. The TD-DFT analysis was also performed to understand electronic transitions and the nature of FMO in these compounds. There was a good correlation found between theoretical and experimental values, thereby confirming the molecular structures of synthesized compounds. Molecular docking studies were performed to obtain more insights on potential anticancer activities of these compounds along with standard anticancer drugs 5-fluorouracil and Tamoxifen against MDM2 (4HG7) protein. The outcome revealed a significant binding affinity of these compounds with target protein even better than 5-fluorouracil and comparable to Tamoxifen. The compounds (INH4 and INH9) having the strongest binding affinity with the target protein are further experimentally evaluated for their in-vitro cytotoxic action on Dalton's lymphoma cells employing MTT assay, fluorescence microscopy, and flow cytometry. IC 50 value (150 µg/ml) of this compound is equated with before-reported complexes/molecules/extracts and found it has better or comparable cytotoxicity. [Display omitted] [ABSTRACT FROM AUTHOR]