Novel vanillin or sulfanilamide derivatives as potential lymphocyte-reducing agents for multiple sclerosis: Design, synthesis, molecular docking, and biological evaluation

Multiple sclerosis (MS) is a chronic autoimmune disorder in which deregulated migration of immune cells leads to demyelination in the central nervous system. Despite the therapeutic success of Fingolimod as the first approved oral drug for MS, its nonspecific interaction with different subtypes of sphingosine-1-phosphate receptors (S1PRs) restricts its clinical use. This study focuses on the rational design of novel S1P 1 receptor modulators containing vanillin or sulfanilamide. The designed compounds were prepared via convenient synthetic routes and characterized using infrared (IR) spectroscopy and nuclear magnetic resonance (NMR) analysis. The lymphocyte-suppressing ability of the synthesized compounds was evaluated in an animal model. Among the studied compounds, compound 5b , administered at 1 mg/kg, produced the greatest lymphocyte decrease, with a 26.53% reduction in lymphocyte counts after 24 h, compared with Fingolimod which produced a 44.43% reduction. Additionally, a molecular docking study was performed using crystallographic structures of S1P 1 , S1P 3 and S1P 5 to validate the theoretical selectivity of the synthesized derivatives toward the S1P 1 subtype. Docking results indicated that all synthesized compounds exhibited a lower ΔG binding for S1P 1 and S1P 5 relative to S1P 3 , with compound 5b (ΔG binding = −7.92 kcal/mol) identified as the best derivative in this series.