3-Substituted Triazolone-Benzoate Hybrids: Synthesis, Enzyme Inhibition, Anticancer Activity and ADMET Evaluation by Molecular Docking and Dynamics Studies

Abstract

In this study, eight 3-substitued -4-amino-4,5-dihydro-1H-1,2,4-triazol-5-one compounds were synthesized. The reactions of these compounds with 2-ethoxy-4-formylphenyl benzoate, which was synthesized by the reaction of 3-ethoxy-4-hydroxy benzaldehyde with benzoyl chloride by using triethylamine, were investigated. Eight novel 2-ethoxy-4-(((3-substitued-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)imino)methyl)phenyl benzoate compounds were obtained in order to identify the new synthesized compounds by spestroscopic methods including IR, 1H-NMR and 13C-NMR used. Concentration ranges of 25, 50, 120, 200, and 400 mu g/mL were applied to determine the compund's anti-cancer properties. The human ovarian cancer cell line (OVCAR-3) compared with human umbilical vein endothelial cells (HUVEC) and significant results were obtained against the OVCAR-3 cell line. The enzyme inhibitory effect of compound on glutathione S-transferase (GST), acetylcholinesterase (AChE) enzymes were studied. Ki and IC50 values were found in the range of 1.1143 +/- 0.2402 mu M-7.9100 +/- 1.9107 mu M and 1.840 mu M-4.149 mu M for AChE; 2.0733 +/- 0.8199 mu M-8.2120 +/- 1.5720 mu M and 1.320 mu M-3.223 mu M for GST. In silico ADMET and drug-likeness analyses confirmed favorable pharmacokinetic and drug-like profiles for the compounds. Additionally, molecular docking and 100 ns molecular dynamics (MD) simulations revealed stable binding modes and dynamic stability of the most active compounds with the target enzymes.