Synthesis Characterization in Silico and in Vitro Anticancer Applications of Heterocyclic Thiosemicarbazones Thiadiazoles and Ru II Arene Complexes

Abstract

A series of heterocyclic thiosemicarbazones (TSCs) derived from polyaromatic hydrocarbons (pyrene and fluorene), specifically PP1, PM1, FP, and FM, along with their cyclized thiadiazole (TDZs) derivatives, PP2, PM2, CFP, and CFM, were synthesized and thoroughly characterized using FT-IR, UV-Visible, NMR, and mass spectrometry. Single crystal XRD analysis confirmed the molecular structures of selected compounds. Additionally, Ru(II)-arene complexes (RuP1P-RuB3P) based on pyrene TSCs were designed and developed. Crystallographic studies revealed that the ligands coordinated preferentially via thionyl sulfur and imine nitrogen to form a distorted octahedral geometry around the Ru(II) ion. Ru(II)-arene complexes (RuPCAP-RuBCAC) with cinnamaldehyde TSCs were also synthesized, and spectroscopic data indicated bidentate coordination through neutral azomethine nitrogen and anionic thionyl sulfur. Additionally, Ru(II)-arene complexes (RuPNPT-RuBNMeT) incorporating 6-nitropiperonal TSCs were prepared and well-characterized. The ground state geometries and electronic properties of the compounds were optimized using the Gaussian 09 program. In silico studies, molecular docking, dynamics, and SwissADME were conducted to evaluate their binding potential and pharmacokinetic properties. The interactions of all compounds with DNA and BSA were examined using absorption, emission spectroscopy, and cyclic voltammetry. The in vitro cytotoxicity of all products was assessed using the MTT assay against various cancer cell lines such as HepG2, T24, A549, HeLa, MCF-7, and MDA-MB-231. The selectivity of the complexes was confirmed by screening their cytotoxicity against normal cell lines such as Vero and MCF-10a. The cell death mechanisms of all active Ru complexes were evaluated through fluorescence staining (AO/EB, DAPI) and flow cytometry. Thus, the in silico and in vitro anticancer applications of heterocyclic TSCs, TDZs, and Ru(II)-arene complexes were comprehensively studied and discussed. newline