From Lipid Regulation to Neuroprotection: Multitarget (Benzo)thiazine Derivatives as Promising Leads

Neurodegenerative and cardiovascular disorders share multifactorial origins, including oxidative stress, (neuro)inflammation, and lipid dysregulation-factors often addressed independently by single-target therapies. In this study, we report a rational multitarget approach through the design and synthesis of novel (benzo)thiazine derivatives that integrate antioxidant, anti-inflammatory, and antihyperlipidemic functionalities within a single molecular framework. The compounds were obtained in good yields via 3-7 step synthetic routes and evaluated through complementary in vitro and in vivo assays. Several derivatives displayed potent inhibition of lipoxygenase (IC₅₀ < 100 μM), significant reduction in carrageenan-induced edema (up to 60%), strong free radical scavenging and lipid peroxidation inhibition, as well as effective iron chelation. In vivo, most derivatives enhanced total antioxidant capacity (by 50-800%) and significantly improved plasma lipid profiles in mouse, while almost all compounds increased the plasma antiatherogenic index by more than 100% with selected compounds exceeding 600%. Notably, several molecules also showed moderate acetylcholinesterase inhibition, suggesting preliminary neuroprotective potential. Altogether, these multifunctional (benzo)thiazine derivatives represent promising lead structures for the development of agents targeting the complex interplay of oxidative, inflammatory, and metabolic pathways underlying neurodegenerative and cardiovascular diseases.