Structural, NBO, HOMO-LUMO Analysis Using DFT and Molecular Docking Analysis of Bioactive 3,4-Difluoroacetophenone-Thiosemicarbazone as a Potential Anticancer Agent

Abstract

The thiosemicarbazone moiety serves as a structural template for the synthesis of a wide variety of N- and S-containing heterocyclic compounds which have proven in-vitro antitumor activity against A549 and MCF-7 cell lines and normal breast and lung cells. In this study, we have reported comprehensive theoretical studies using density functional theory (DFT) on molecular structure, molecular electrostatic potential (MEP), Natural Bond Analysis (NBO) and HOMO-LUMO analysis of an important thiosemicarbazone compound 3,4-difluoroacetophenone-thiosemicarbazone (DFAT). Pale yellow crystals were recently synthesized by mixing of 3,4-difluoroacetophenone and thiosemicabazide ethanolic solution and then crystallized by slow evaporation process. Anti-tumor activity of DFAT ligand was explained in terms of intra-molecular charge delocalization which gives insight into inter and intra-molecular interactions. Molecular docking studies of DFAT verified its inhibitory nature against 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) (PDB ID: 3HB5) protein associated with cancer disease. From docking studies, it is found that the titled molecule exhibits a maximum binding affinity of −5.9[Formula: see text]kcal/mol with respect to the target protein. Three hydrogen bonds were formed with residues SER11 having the bond distances 3.00[Formula: see text]Å, 2.50[Formula: see text]Å and 2.34[Formula: see text]Å respectively. The DFAT molecule also shows hydrogen bonding with ASP65, THR190 and GLY15 residue with a bond distance 2.02[Formula: see text]Å, 2.05[Formula: see text]Å and 1.83[Formula: see text]Å respectively. A comparative study of the titled molecule with other several thiosemicarbazone derivatives shows that DFAT has good binding affinity than that of referenced drugs and can be used as a more potent active pharmaceutical ingredient (API) for cancer treatment.