Synthesis, Spectroscopic Characterization, Molecular Docking Studies Toward the GABAA Receptor, ADMET Prediction, GABA Aminotransferase Inhibition, and Anxiolytic Evaluation of Novel Thiazine Derivatives.

Background

The current study uses a computational technique to investigate synthesized thiazine compounds that exhibit potential interactions with the GABAA receptor. A series of novel thiazine derivatives was synthesized via the cyclization reaction of chalcone with thiourea.

Methods

For the synthesized compounds, spectroscopic characterization, namely FT-IR, 1H NMR, 13C NMR, and mass spectrometry, was carried out. In addition, the AutoDock Vina 4.2 software was applied to carry out an in silico docking study.

Results

The synthesized compounds C3 and C6 exhibited comparable predicted docking scores (-9.0 and -9.1 kcal/mol, respectively), with favorable predicted interactions at the GABAA receptor binding site. Furthermore, in silico ADMET analysis provided insights into the drug-likeness and pharmacokinetic profiles of the synthesized compounds; however, potential safety liabilities, including Ames positivity, hERG II liability, and hepatotoxicity, were predicted for some derivatives.

Conclusions

It was determined that the synthesized compounds' various physiologically significant and physiologically relevant parameters fell within the range of Lipinski's rule of five. The synthesized compounds (C1-C10) were tested for anxiolytic activity by the elevated plus maze test, and compound C6 was found to be the most potent. Additionally, the in vitro GABA-AT enzyme activity assay showed that compound C6 had the highest inhibitory potential, with an IC50 of 13.29 ± 1.622 µM.