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.