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.