Synthesis, biological evaluation and molecular dynamics studies of oxadiazine derivatives as potential anti-hepatotoxic agents

Abstract

Generally, herbal medicines having remarkable popularity for treating liver ailments, but they are still unacceptable because of the deprivation of herbal drug standardization. Therefore, there is a need for promising synthetic drugs to overcome the critical liver problem. We introduce 1, 3, 4-oxadiazine ring in this study to identify better anti-hepatotoxic agents via a suitable synthetic route. These oxadiazine-based derivatives were structurally confirmed by analytical and spectral data and evaluated for their anti-hepatotoxic potential. Further, <i>in vitro</i> hepatotoxicity studies have been done to check the toxicity level in the synthesized compound. Compounds <b>5a</b>, <b>5b</b>, <b>5c</b> and <b>9d</b> were selected for further biological evaluation according to <i>in vitro</i> results. After that, CCl₄-induced animal model was used to evaluate <i>in vivo</i> anti-hepatotoxicity activity. Compound <b>5a</b> with 52.99%, 59.3%, 79.34% and <b>5b</b> with 52.16%, 57.65%, 75.10% revealed to be most promising for reduction in level of SGPT, SGOT and ALKP, respectively. Moreover, it was also observed that the compound <b>5a</b> with 411.01%, 53.39% and <b>5b</b> with 378.63%, 48.9% level of albumin and total protein were respectively. The induced-fit docking results of the compounds <b>5a</b> and <b>5b</b> reveal some essential binding information and exhibited desirable ADME properties, and obeyed Lipinski's rule of five. In addition, molecular dynamics studies for 100 ns further confirm the protein-ligand complex's stability, supporting the <i>in vitro</i> and <i>in vivo</i> data, and help in establishing the SAR of synthesized compounds. Two compounds, <b>5a</b> and <b>5 b</b>, exhibited higher anti-hepatotoxic activity than the standard drug silymarin.