Synthesis, investigation of the crystal structure, DFT calculations, and in silico medicinal potential of hydrazono- and aminomethylene substituted pyrazolidine-3,5-diones as potential anticancer scaffolds

Abstract

Two new pyrazolidine-3,5-dione derivatives namely (Z)-4-(2-(4-bromophenyl)hydrazono)-1-phenylpyrazolidine-3,5-dione (2) and (E)-1-phenyl-4-((pyridin-2-ylamino)methylene)pyrazolidine-3,5-dione (3) were synthesized and their structures were elucidated by single-crystal X-ray analysis along with spectroscopic techniques. Density functional theory (DFT) studies were carried out to examine the distribution of charge, and natural bond orbital (NBO) analysis and frontier molecular orbital (FMO) analysis were carried out. Hirshfeld surface analysis was carried out to examine the intermolecular interactions, revealing a prevalence of H⋯H interactions in the crystals of both molecules. NBO analysis was carried out to investigate the stabilization energy, while MEP analysis was conducted to explore regions susceptible to nucleophilic and electrophilic attacks. The molecules were screened for their medicinal potential based on physiochemical and pharmacokinetics including (gastrointestinal) GI absorption, blood brain barrier (BBB) permeation, skin permeation capability, Caco-2 permeability, Madin–Darby canine kidney (MDCK) permeability, drug metabolism by the cytochrome P450 (CYP) family of liver enzymes, and toxicity evaluations. The expected metabolic reactions in the real cell system and the resulting metabolites along with their polarities for the determination of the probability of excretion from the body and drug-likeness were studied. To investigate the anticancer potency of 2 and 3, both were docked with three enzymes as drug targets for anticancer studies including HER2 (PDB ID: 3WSQ), EGFR (PDB ID: 5WB7), and the extracellular domain of the Tdp enzyme (PDB ID: 6N0D). From the calculated binding energies and inhibition constants, 2 is a better inhibitor of the target substrates than 3.