Anticancer activity, DNA binding and docking study of M(ii)-complexes (M = Zn, Cu and Ni) derived from a new pyrazine–thiazole ligand: synthesis, structure and DFT

Abstract

A series of structurally related Zn(II), Cu(II) and Ni(II) complexes of 4-(2-(2-(1-(pyrazin-2-yl)ethylidene)hydrazinyl)-thiazol-4-yl)-benzonitrile (PyztbH) have been synthesized and characterized by spectroscopy, single crystal X-ray crystallography and density functional theory (DFT). All the complexes are mononuclear and the molecular composition of the complexes viz. [Zn(Pyztb)₂] (1), [Zn(PyztbH)(SCN)₂] (2), [Cu(Pyztb)(N₃)(MeOH)] (3) and [Ni(Pyztb)(PyztbH)]ClO₄ (4) is confirmed by single crystal X-ray crystallography. The interaction of the compounds with calf thymus DNA (CTDNA) was studied by various spectroscopic methods (UV-Vis and fluorescence) and molecular docking study. Both the binding constant (k_b) and the Stern–Volmer dynamic quenching constant (K_SV) values of the compounds are in the order of 10⁴ indicating the intercalative binding mode of the compounds with CTDNA. The molecular docking study revealed that PyztbH, 1 and 3 are well fitted in the active sites of DNA having higher binding affinity than 2 and 4. All the synthesized compounds are assessed for anticancer activity towards different human cancer cell lines having different tissue origin e.g., U-937 (histiocytic lymphoma), HepG2 (hepatic carcinoma), HEK293T (embryonic kidney), U2OS (osteosarcoma), HeLa (cervical epithelium), A549 (lung carcinoma) and A431 (squamous carcinoma). The thiazole–pyrazine ligand shows relatively less cytotoxicity toward the tested cell lines than its metal derivatives. MTT assays reveal that 1 (IC₅₀ values 1.5 to 21 μM) and 3 (IC₅₀ values 1.0 to 15 μM) showed higher cytotoxicity than 2 (IC₅₀ values 1.0 to 126 μM) and 4 (IC₅₀ values 9 to 106 μM) across the cell types. Both 1 and 3 follow the necroptotic pathway of cell death, whereas 2 and 4 follow the apoptotic pathway. Peripheral blood mononuclear cell (PBMC) assay of 1, 2 and 4 revealed nontoxicity in normal blood cells.