The Cytotoxic Effect on HepG2 Cell Line and in Vitro, in Silico Evaluation of 1,2,4-Triazine Compounds as Inhibitors of Acetylcholinesterase and Glutathione S-Transferase

Abstract

The inhibitory effects of several 1,2,4-triazine compounds (Tr-1, Tr-2, Tr-3) on acetylcholinesterase (AChE) and glutathione S-transferase (GST) enzymes were explored. IC50 values for 1,2,4-triazine compounds were determined, ranging from 2.45 to 9.91 mu M for AChE and from 3.98 to 8.45 mu M for GST. Moreover, Ki values for for 1,2,4-triazine compounds were found, ranging from 0.6733 +/- 0.0321 to 4.3690 +/- 0.121 mu M for AChE and from 3.7997 +/- 1.0124 to 10.613 +/- 0.7132 for GST. The results indicated that the inhibitory activity of Tr-1, Tr-2, and Tr-3 was comparable to the standard inhibitor Tacrine (Tac) and Ethacrynic acid (INN), respectively. To determine the anticancer properties of these molecules, their cytotoxic effects on a human liver cancer cell line (HepG2) were investigated. It was observed that Tr-2 was the most effective molecule among the 24, 48, and 72nd hours. MTT colorimetric assay was used for in vitro cytotoxicity study. The molecular docking studies demonstrated the stability of between selected proteins and Tr-1, Tr-2, Tr-3 molecules' complexes and provided detailed insights into these compounds-protein interactions at the molecular level. These findings formed the foundation for biologic activity these compounds with optimized binding properties and anticipated inhibitory activities. Additionally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of the Tr-1, Tr-2, Tr-3 molecules were conducted to obtain deeper insights into ADMET properties in AChE and GST candidate inhibitors.