Abdul_2026_Future.Med.Chem__1

AIM: To synthesize novel sulfonohydrazide derivatives and evaluate their physicochemical and enzymeinhibitory profiles, together with the corresponding structure-activity relationships. METHODS: A series of six hydrazide derivatives (NLs(1)-NLs(6)) was synthesized and subjected to comprehensive in vitro enzymatic evaluation against four critical targets: 15-Lipoxygenase (15-LOX), Carbonic anhydrase II (beta-CA-II), Butyrylcholinesterase (BChE), and Acetylcholinesterase (AChE). Furthermore, to determine the stability and binding of the synthesized compounds, molecular dynamic simulations and molecular docking were performed. RESULTS: Bromo- and fluoro-substituted NLs(2) (IC(50) = 0.29 +/- 0.02 microM) and NLs(3) (IC(50) = 0.54 +/- 0.01 microM) showed significant activity against AChE. Furthermore, compound NLs(4) demonstrated significant cholinesterase inhibitory activities, i.e. AChE and BChE, although the inhibitory potential against AChE (IC(50) = 0.72 +/- 0.11 microM) was comparatively higher than that of BChE (IC(50) = 0.65 +/- 0.03 microM). MD trajectories of all three systems involving proteins and NLs(3) indicate that AChE-NLs(3) exhibit the highest level of overall structural stability, closely followed by LOX-NLs(3) as both have a low RMSD amplitude and low residue variations. CONCLUSION: These findings identify several derivatives as promising multi-target lead compounds for the treatment of diseases driven by the dysregulation of lipid metabolism, cholinergic signaling, and carbonic anhydrase activity.