Prediction by DFT and synthesis of new xanthene derivatives: Evaluation of their toxicity and antihyperlipidemic properties in-vivo and in-silico

Abstract

The current research focuses on the synthesis of novel Xanthene-based heterocyclic compounds and the evaluation of their toxicity and antihyperlipidemic effect. Our approach consists of exploring this synthesis and its mechanism theoretically via DFT calculations, and carrying out the synthesis in the laboratory. The Xanthene derivatives were synthesized by O-p-methylbenzylation and O-benzoylation, and their structures were established using standard spectroscopic methods. The experimental results obtained are in good agreement with the theoretical data. Furthermore, the synthetized Xanthene compounds were evaluated for their acute oral toxicity, and the results suggest the safety of oral administration of these compounds at a dose equal to or less than 2000 mg/kg. These Xanthene derivatives were then evaluated in Triton-induced hyperlipidemic rats and their effects were compared to those of the norm. They were found to have good antihyperlipidemic activity, comparable to that of the marketed antihyperlipidemic drug. In addition to in vivo investigations, in silico studies involving molecular docking and molecular dynamics (MD) simulations, as well as ADME analyses, were carried out to support and explain the experimental results. Additionally, docking results showed that the compounds exhibited robust binding interactions with key residues of the target receptor. Furthermore, the stability of the formed ligand-protein complexes was demonstrated through 100 ns MD simulations. Lastly, the prediction of ADME properties shows that Xanthene compounds possess good and favorable pharmacokinetic profiles.