New thiazine derivatives with dual potential for lipoxygenase inhibition and hemolytic activity: Synthesis, characterization and molecular docking studies.

Inflammation-related disorders remain a major health challenge, driving the need for safer and more effective therapeutic agents. Targeting lipoxygenase inhibition while monitoring hemolytic safety, this work presents the synthesis and biological evaluation of novel thiazine (4a-o) derivatives by chalcone-ring closure with thiourea bearing different substituents. Physical properties and spectroscopic methods were utilized to characterize the products. Their biological activity was determined by in vitro inhibition assays of soybean lipoxygenase and hemolytic activity. All analogues showed varying degree of lipoxygenase inhibitory potential in the range of 34.3 ± 0.4-191.3 ± 0.6 µM in comparison to standard inhibitor quercetin with IC50 value 2.3 ± 0.3 µM. Among the series, analogs 4c, 4d and 4e with IC50 value 34.7 ± 0.5, 43.5 ± 0.5 and 41.3 ± 0.4 µM respectively showed potent lipoxygenase inhibitory potential. Hemolytic activity for 4c, 4d and 4e was also in low to moderate range as 42.3 ± 1.4, 34.5 ± 1.9 and 43.1 ± 1.2 µM respectively with 0.5 mM conc. Molecular toxicity profiling of compounds 4c, 4d, and 4e against reference Quercetin using Pro Tox 3.0, reveals toxicity class, LD50, receptor binding profile, and organ specific effects. Contrasting with Quercetin reveals significance toxicity profile, ADMET, and physiological, highlighting critical insights for lead optimization. Moreover, in silico molecular docking studies were also conducted to study the binding interactions of the synthesized 1,3-thiazine derivatives towards the lipoxygenase (LOX) enzyme. In silico results validated the in vitro results and also gave more insight into the likely mode of inhibition. In total, the research reports the promising potentiality of these 1,3-thiazine derivatives as potential lipoxygenase inhibitors with complementary biochemical and computational information.