Nickel(II) Complexes with Polyhydroxybenzaldehyde and O,N,S tridentate Thiosemicarbazone ligands: Synthesis, Cytotoxicity, Antimalarial Activity, and Molecular Docking Studies

Abstract

A series of Schiff base metal complexes with the formulations [Ni(L1)PPh3]Cl (1), [Ni(L2)PPh3]Cl (2), [Ni(L3)PPh3] (3), and [Ni(L4)PPh3] (4) (where L1 = 2,3,4-trihydroxybenzaldehyde-4-methyl-3-thiosemicarbazone, L2 = 2,3,4-trihydroxybenzaldehyde-4-ethyl-3-thiosemicarbazone, L3 = 2,3,4-trihydroxybenzaldehyde-4-phenyl-3-thiosemicarbazone, and L4 = 2,3,4-trihydroxybenzaldehyde-4-(4-ethylphenyl)-3-thiosemicarbazone) were synthesised. All compounds were characterised using FT-IR, 1H NMR, and 13C NMR. The complexes were further characterised with single crystal X-ray diffraction. The complexes are four-coordinated and adopt a square planar geometry, in which the Schiff base ligands bind to the metal centre via their tridentate O,N,S atoms. Ligand L2 and complex 1 showed a higher cytotoxic activity than cisplatin with IC50 5.75 ± 0.49 and 4.26 ± 0.29 μM, respectively when tested against human colorectal carcinoma HCT 116. Besides, complex 3 was found to show a stronger cytotoxic activity with an IC50 7.07 ± 0.61 μM than its ligand (L3 IC50 9.82 ± 1.85 µM) when tested against HCT 116. On the other hand, complexes 2 and 3 showed moderate in vitro antimalarial activity with IC50 9.88 ± 0.23 and 1.06 ± 0.01 μM, respectively. Remarkably, the antimalarial activity increases as the hydrophobicity of the substituent group attached at the N(3) position increases. Through molecular docking simulation, complexes 2 and 3 are predicted to be a minor groove binder with an appreciable DNA binding affinity, suggesting that 2 and 3 exerted their cytotoxicity and antiplasmodial activity probably via their benzaldehyde, triphenylphosphine, aliphatic chain and phenyl moieties interaction with DNA base pairs.