Rational design and synthesis of Co(ii), Ni(ii) and Cu(ii) complexes bearing 1,2,4-triazole scaffold for biological...

The chemistry of 1,2,4-triazole-incorporating compounds and their metal complexes has attracted widespread attention due to their potential therapeutic activities. Therefore, this paper presents the synthesis, characterization, biological studies, and theoretical molecular docking evaluation of 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole (AHMT) and its Co(ii), Ni(ii), and Cu(ii) complexes. The proposed structures were confirmed by elemental and spectroscopic analyses, yielding trans-N₂S₂ in an equatorial arrangement within an octahedral geometry. Numerous biological studies have been conducted on AHMT, Co(ii)-AHMT, Ni(ii)-AHMT, and Cu(ii)-AHMT. The synthesized scaffolds have been screened for their antibacterial activity against various bacterial and fungal species. Notably, Ni(ii)-AHMT is more potent than the other hybrids. Indeed, the cytotoxic activity of the synthesized hybrids was assessed against four human cancer cell lines: HePG2, MCF-7, HeP-2, and HeLa. The findings revealed that Ni(ii)-AHMT has the most toxicity with IC₅₀ values of 8.70 ± 0.5 µM and 9.72 ± 0.7 µM against MCF-7 and HeLa cell lines, respectively. The enhanced antimicrobial and anticancer activities of the metal complexes relative to the free AHMT ligand are attributed to Tweedy's chelation theory, which explains that reduced metal polarity increases lipophilicity and membrane penetration. Mechanistic studies revealed that Ni(ii)-AHMT induces cell death primarily via apoptosis and causes prominent G0/G1 cell-cycle arrest in MCF-7 cells. DNA-binding assays of the synthesized compounds were performed. Additionally, the activity of superoxide dismutase (SOD) in the compounds has also been evaluated using the NBT assay. The free ligand AHMT and its nickel complex Ni(ii)-AHMT demonstrate notable radical-scavenging capacity, achieving 75.8% and 70.2% inhibition, respectively, compared to the reference antioxidant l-ascorbic acid (78.2%). Molecular docking experiments were conducted to understand the binding interactions of AHMT and its metal complexes with DNA, β-lactamase, and human serum albumin. The docking simulations were consistent with the in vitro findings and suggested that Ni(ii)-AHMT is a potential DNA groove binder and a potent antimicrobial candidate that merits further in vivo investigations.