Biochemical Resistivity against Free Radicals and Microbes: Cooperative Action of Zn(II)/Imidazole in Phosphoesterase-Mediated Cell Death.

Abstract

This work delivers a targeted synthesis of four isostructural O-substituted imidazole-based zinc(II) complexes, namely, [Zn2(L1)2(I)2](DMF) (1), [Zn2(L2)2(I)2](DMF) (2), [Zn2(L1)2(Br)2] (3), and [Zn2(L2)2(Br)2] (4), derived from homologous Schiff-base ligands HL1 and HL2 to explore their impact on free radicals, microbes, and dephosphorylation of phosphoesters. The antioxidant activity of all complexes was checked by various radical scavenging assays (ABTS+•, DPPH•, and H2O2 radical quenching). Among them, complex 2 showed superior radical quenching activity, as indicated by its lowest EC50 value and thus maximum antioxidative capability. Again, antibacterial assays against several Gram-positive and Gram-negative bacteria were conducted to evaluate the zone of inhibition. The minimum bactericidal concentration and minimum inhibitory concentration values from the microdilution method for all complexes revealed complex 3 to have maximum potency against Gram-positive bacteria. The P-O bond hydrolysis in the phospholipid chain caused by the hydrolytic phosphoesterase activity of the Zn(II)-complexes plays a crucial role in cell membrane rupture. A model substrate 4-PNPP was used to explain the potency of monomeric Zn(II) complex (3) for cell penetration over dimeric one (2) with a proper mechanism. Furthermore, a heme model substrate, Fe(TPP)Cl, has been introduced with the most potent complex 3 and has spectrophotometric evidence for covalent interaction with imidazole and Fe(III) that can disrupt the nitric oxide dioxygenase function of flavohemoglobin, leading to bacterial cell death. To our knowledge, this is the first case to report a novel mechanism of antimicrobial action where both the metal and the ligand are cooperatively involved in bacterial cell death. The main goal of this work is to invent multifunctional therapeutics as well as the proper chemical rationalization of biological processes using mechanistic approaches, which includes investigating the roles of halides, imidazoles, and solution-phase structural variations of complexes..