One pot synthesis of 5-hydroxyalkylated thiadiazine thiones: Implication in pain management and bactericidal properties

The synthesis of a new series of thiadiazine thiones including 5-(2-hydroxyethyl)-3-alkyl/aryl-1, 3, 5-thiadiazine-2-thiones (1-5), 5-(2-hydroxypropyl)-3-alkyl/aryl-1, 3, 5-thiadiazine-2-thiones (6-8), 3,5-dipropyl-1, 3, 5-thiadiazine-2-thione (9) and (2-(5-alkyl/aryl-6-thioxo-1, 3, 5-thiadiazine-3-yl) alkyl acetate/benzoate) (10-17) was accomplished via one pot reaction. The structures of the synthesized compounds were characterized through NMR and Mass spectrometry. The anti-nociceptive activity of compounds was performed on BALB/C mice by hot plate method, where compounds 3, 5 (50 μg/kg), and 8 (50, 100 μg/kg) exhibited significant effect (P ˂ 0.01, P ˂ 0.05) in latency time of 15, 30 and 60 min, while compounds 6 and 16 (100 μg/kg) exhibited significant effect (P ˂ 0.01, P ˂ 0.05) in latency time interval of 15 and 30 minutes, and 1, 12-13, and 15 showed moderate activity. Among the tested hits, compounds 5 (17.3 ± 2.2), 11 (16.2 ± 2.1) and 8 (16.1 ± 2.1) showed significant anti-nociceptive potential. The binding potential of the most active anti-nociceptive hits was demonstrated by molecular docking, which revealed these compounds may target μ-opioid receptor (μOR) effectively to elicit their anti-nociceptive activity. Furthermore, compounds 14 and 11 showed anti-bacterial activity against Pseudomonas aeruginosa and MSRA with MIC of 40.97 and 54.77 μg/mL, respectively. In addition, the predicted ADMET profile of 5, 9, and 11 indicates that these molecules follow the drug-likeness criteria, and their activity can be enhanced structural optimization.