Effect of N-benzyl group in indole scaffold of thiosemicarbazones on the biological activity of their Pd(II) complexes: DFT, biomolecular interactions, in silico docking, ADME and cytotoxicity studies

A series of N-benzyl substituted indole-based thiosemicarbazone (TSC) ligands (L4-L6) and palladium(II) TSC complexes, [Pd(L)₂] (1–6) (L = monoanionic bidentate un/N-substituted indole-based TSC ligand) have been synthesized and characterized using analytical and spectroscopic tools. The exact molecular structures of L4-L6 and the complexes (2–4 and 6) were ascertained by single-crystal X-ray diffraction (XRD) method. Spectroscopic and crystallographic studies indicated that Pd(II) ion was coordinated with TSCs as monobasic bidentate ligands, forming two five-membered rings with square planar geometry. The effect of N-benzyl substitution in indole scaffold of TSCs in the complexes was studied using DFT method, and structure–activity relationships (SAR) were explored. The in silico ADME properties of the ligands and their complexes were thoroughly analyzed with respect to their lipophilicity and oral bioavailability. The complexes (1–6) exhibited strong intercalation with calf thymus DNA (CT DNA), which was examined by absorption/emission spectroscopic titrations and viscosity measurements. Similarly, the interaction of bovine serum albumin (BSA) with complexes examined using spectroscopic methods showed a strong binding between them. A better picture of various possible interactions was acquired from the molecular docking of the complexes with the targets like DNA, BSA, DNA Topoisomerase II and CASP3. In addition, in vitro cytotoxicity of the complexes was screened against two cancer (HeLa-S3 and A549) and one normal (IMR-90) cell lines. It was learnt that the N-benzyl substitution in the indole system inactivated the whole molecule by diminishing its anticancer activity. The unsubstituted indole TSC complex (2) displayed significant activity towards HeLa-S3 cells, and the results were compared with those of cisplatin. Beneficially, the active complex showed less toxicity against IMR-90 normal cells. Further, the results of AO-EB staining studies indicated that the complexes induced cell death via apoptosis pathway. The steric influence of the substituted indole moiety, its limited electronic effects and lesser stability in aqueous systems retarded the Pd(II) complexes of N-benzyl substituted indole TSCs from exhibiting their biological activities.