Exploration of newly synthesized sulfonohydrazides as potential enzyme inhibitors: synthesis, characterization, and in silico studies

Aim To synthesize novel sulfonohydrazide derivatives and evaluate their physicochemical and enzyme‑inhibitory profiles, together with the corresponding structure-activity relationships.Methods A series of six hydrazide derivatives (NLs1-NLs6) was synthesized and subjected to comprehensive in vitro enzymatic evaluation against four critical targets: 15-Lipoxygenase (15-LOX), Carbonic anhydrase II (β-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 NLs2 (IC50 = 0.29 ± 0.02 µM) and NLs3 (IC50 = 0.54 ± 0.01 µM) showed significant activity against AChE. Furthermore, compound NLs4 demonstrated significant cholinesterase inhibitory activities, i.e. AChE and BChE, although the inhibitory potential against AChE (IC50 = 0.72 ± 0.11 µM) was comparatively higher than that of BChE (IC50 = 0.65 ± 0.03 µM). MD trajectories of all three systems involving proteins and NLs3 indicate that AChE-NLs3 exhibit the highest level of overall structural stability, closely followed by LOX-NLs3 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.