Syntheses, quantum mechanical modeling, biomolecular interaction and in vitro anticancer – Tubulin activity of thiosemicarbazones

[Display omitted] A new series of thiosemicarbazones were designed and synthesized. Their structures were confirmed by spectral characterization and single crystal XRD studies. Compounds MTSC-2 and ETSC-3 crystallized in the orthorhombic crystal system with space group Pbc21 andPca21respectively. Density functional theory computational studies were performed on MTSC-2 and ETSC-3 along with natural bond orbital analysis and Mulliken population analysis to study the structural and electronic properties of the thiosemicarbazones. The HOMOs of the two thiosemicarbazones are −5.2943 and −5.1133 eV respectively while the LUMOs are −1.6879 and −1.6398 eV respectively. The energy gap is 3.6064 and 3.4736 eV respectively. Molecular docking studies were performed to determine the binding mode of the thiosemicarbazones against β-tubulin. The theoretical studies were further supplemented with tubulin polymerization inhibition assay. All the four thiosemicarbazones proved effective in inhibiting the polymerization of α- and β-tubulin heterodimers into microtubules. The anticancer activity of these compounds showed their extreme potency against A549 and HepG2 cancer cell lines with IC50 values of 0.051 – 0.189 µm and 0.042 – 0.136 µm respectively. Compound PTSC-4 showed the highest activity both against tubulin and the two cancer cell lines. This was in correlation with the theoretical studies. Hence, these four compounds, specifically PTSC-4, can be considered to be potential leads in the development of non-metallic anticancer agents.