Novel Mono-Substituted 4H-1,2,6-Thiadiazines with Antioxidant and Anti-Lipoxygenase Activities

Τhe synthesis of a novel series of mono-substituted 4H-1,2,6-thiadiazine derivatives was reported, aiming at enhancing antioxidant and lipoxygenase inhibitory activities via pharmacophore combination. The compounds were prepared from 3,5-dichloro-4H-1,2,6-thiadiazin-4-one and 2-(3,5-dichloro-4H-1,2,6-thiadiazin-4-ylidene)malononitrile. All the derivatives were evaluated for radical scavenging activity towards 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azobis(2-methylpropionamidine) dihydrochloride (AAPH)-induced lipid peroxidation inhibition, and soybean lipoxygenase (sLOX) inhibition. The compounds exhibited moderate to good antioxidant activity and variable sLOX inhibition. Notably, 2-[3-(benzo[d]oxazol-2-ylthio)-5-chloro-4H-1,2,6-thiadiazin-4-ylidene]malononitrile showed the strongest antioxidant effect (92% DPPH scavenging at 60 min and 70% inhibition of AAPH-induced lipid peroxidation) but low sLOX inhibition, whereas 3-chloro-5-(4-phenylpiperazin-1-yl)-4H-1,2,6-thiadiazin-4-one displayed the most potent sLOX inhibition (IC50: 7.5 μM), with a docking score of −8.3 kcal/mol developing hydrophobic interactions with Phe134 and Val520.