Effect of the extended π-surface and N-butyl substituents of imidazoles on their reactivity, electrochemical behaviours and biological interactions of corresponding Pt(<sc>ii</sc>)-CNC carbene complexes: exploring DFT and docking interactions

In this study, we synthesised and characterised three C<^>N<^>C pincer (N-heterocyclic carbene)-type tridentate ligands, namely, 2,6-bis[(3-methylimidazolium-1-yl)methyl]pyridine dibromide (L-1), 2,6-bis[(3-methylbenzimidazolium-1-yl)methyl]pyridine dibromide (L-2) and 2,6-bis[(3-butylimidazolium-1-yl)methyl]pyridine dibromide (L-3), and their corresponding six-membered chelates with Pt(II) to form PtL1-PtL3 complexes, namely, 2,6-bis[(3-methylimidazolium-1-yl)methyl]pyridinechloroplatinum(II) tetrafluoroborate (PtL1), 2,6-bis[(3-methylbenzimidazol-1-yl)methyl]pyridinechloroplatinum(II) tetrafluoroborate (PtL2) and 2,6-bis[(3-butylimidazol-1-yl)methyl]pyridinechloroplatinum(II) tetrafluoroborate (PtL3). Substitution kinetics using thiourea nucleophiles (tu, dmtu and tmtu), structural properties through theoretical DFT, biological interactions with DNA/BSA, electrochemical behaviors using cyclic voltammetry and docking simulations for Pt(II) C<^>N<^>C pincer complexes were investigated. The extended pi surface of benzimidazole (PtL2) caused sigma-donation in cis-Pt-C bonds, while N-butyl arms (PtL3) on the bis(3-methylimidazolium-1-yl)pyridine C<^>N<^>C pincer ligand had a steric influence on the labile ligand, leading to an increasing order of chloride substitution as follows: PtL3 < PtL2 < PtL1. The nucleophile's reactivity order is in accordance with its bulkiness, and the order is tu > dmtu > tmtu. Reactivity trends were justified by the trends in theoretical DFT data. Strong cis sigma-donor ligands prevent the co-coordination of the spectator ligand. Large negative entropy of activation (Delta S-#) and positive enthalpy of activation (Delta H-#) support a limiting associative substitution mechanism. Biological interactions of PtL1-PtL3 with CT-DNA and BSA complexes were confirmed using spectroscopic and cyclic voltammetry (CV) titrations, and the data obtained established moderate-to-strong binding affinities. Complexes bind to CT-DNA mainly via the groove mode and to a lesser extent via intercalation, whereas they insert into the upper protein cleft of BSA. Electrochemistry results also established the groove binding mode of interaction, and -Delta G values affirmed the binding process as spontaneous. Molecular docking simulations of PtL1-PtL3 with CT-DNA and BSA corroborated with groove binding being the main binding mode.