New Sulfonate-Semicarbazone Hybrid Molecules: Synthesis, Theoretical Evaluations, Molecular Simulations, and Butyrylcholinesterase Inhibition Activity

In the present work, 18 novel semicarbazone-sulfonate hybrids were synthesized to evaluate their potential as butyrylcholinesterase (BChE) inhibitors. Among all compounds, 4-[(<i>E</i>)-(2-carbamoylhydrazinylidene)-methyl]-phenyl 2-(trifluoromethoxy)-benzene-1-sulfonate (<b>12</b>), 4-[(<i>E</i>)-(2-carbamoylhydrazinylidene)-methyl]-phenyl naphthalene-1-sulfonate (<b>17</b>), and 4-[(<i>E</i>)-(2-carbamoylhydrazinylidene)-methyl]-phenyl naphthalene-2-sulfonate (<b>18</b>) exhibited the most potent BChE inhibition, with IC₅₀ values of 61.88, 77.02, and 93.67 μM, respectively, outperforming the reference drug pyridostigmine bromide (IC₅₀: 130.04 μM). As shown by molecular docking studies, numerous interactions, including hydrogen bonds, π-π stacking, π-sulfur contacts, and halogen bonds, supported the high binding of compounds' affinities to the BChE active site. Also, this study employed molecular dynamics (MD) simulations to assess the inhibitory potential of compounds <b>12</b>, <b>17</b>, and <b>18</b> against BChE. All ligands retained structural integrity during simulations. Compound <b>17</b> exhibited the highest conformational stability (minimal RMSD values) and formed robust interactions with critical binding site residues. Additionally, compound <b>18</b> demonstrated superior hydrogen bonding capacity, while compound <b>17</b> achieved the strongest binding affinity. Furthermore, <i>in silico</i> ADME predictions for the most active molecules showed good pharmacokinetic profiles and drug-likeness. Consequently, the results suggested that semicarbazone-sulfonate hybrid compounds <b>12</b>, <b>17</b>, and <b>18</b> were promising potential multifunctional agents targeting cholinergic dysfunction in Alzheimer's disease (AD).