Instigating the In Vitro Anticancer Activity of New Pyridine-Thiazole-Based Co(III), Mn(II), and Ni(II) Complexes: Synthesis, Structure, DFT, Docking, and MD Simulation Studies

The perchlorate salt of (4-(4-methoxy phenyl)-2-(2-(1-pyridine-2-yl)ethylidene)hydrazinyl)thiazole (PytHmiddotClO4) and its metal perchlorate derivatives,namely, [Co(Pyt)2]ClO4(1), [Mn(PytH)2](ClO4)2(2), and [Ni(PytH)2](ClO4)2(3), have been synthesized and characterized through single X-ray crystallography andspectroscopic methods. The ligand crystallizes in a space groupP21/nin a nearlyplanar structure. The overall geometry of the complex salts is described as a distortedoctahedron with a MN6chromophore. The ligand (PytHmiddotClO4)behaves as a neutralN,N,N-tridentate donor toward the"soft"Mn(II) and Ni(II) centers, whereas thedeprotonated ligand stabilizes the"hard"Co(III) center. The DNA binding constant(Kb) values ofPytHmiddotClO4,1,2, and3are determined using the UV-vis spectroscopicmethod, and theKbvalues are 9.29x105, 7.11x105, 8.71x105, and 7.82x105mol-1, respectively, indicating the intercalative mode of interactions with CT-DNA. Allthe derivatives show effective antiproliferative activity against U-937 human monocytictumor cells with IC50values 4.374 +/- 0.02, 5.583 +/- 0.12, 0.3976 +/- 0.05, and 11.63 +/- 0.01 mu M forPytHmiddotClO4,1,2, and3, respectively. The best apoptosis mode of cell death is shown by2followed byPytHmiddotClO4and1at an equivalent concentration of IC50values. The combined molecular docking and dynamics simulation study evaluates the bindingenergies of anticancer agents, providing groove binding property with DNA. The 20 ns molecular dynamics simulation study revealsthe maximum DNA binding stability of2corroborating the experimental results. The new class of metal derivatives of pyridine-thiazole can be used for advanced cancer therapeutics