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

## TL;DR

Scientists created new hybrid molecules that strongly inhibit an enzyme linked to Alzheimer's disease, showing potential as drug candidates.

## Contribution

The study introduces novel semicarbazone-sulfonate hybrids with potent butyrylcholinesterase inhibition and favorable drug-like properties.

## Key findings

- Three compounds (12, 17, and 18) showed stronger BChE inhibition than the reference drug pyridostigmine bromide.
- Molecular docking and MD simulations revealed strong interactions and stability of the compounds in the BChE active site.
- In silico ADME predictions indicated good pharmacokinetic profiles and drug-likeness for the most active molecules.

## Abstract

In the present work, 18 novel semicarbazone-sulfonate
hybrids were
synthesized to evaluate their potential as butyrylcholinesterase (BChE)
inhibitors. Among all compounds, 4-[(E)-(2-carbamoylhydrazinylidene)­methyl]­phenyl
2-(trifluoromethoxy)­benzene-1-sulfonate (12), 4-[(E)-(2-carbamoylhydrazinylidene)­methyl]­phenyl naphthalene-1-sulfonate
(17), and 4-[(E)-(2-carbamoylhydrazinylidene)­methyl]­phenyl
naphthalene-2-sulfonate (18) 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 12, 17, and 18 against BChE. All
ligands retained structural integrity during simulations. Compound 17 exhibited the highest conformational stability (minimal
RMSD values) and formed robust interactions with critical binding
site residues. Additionally, compound 18 demonstrated
superior hydrogen bonding capacity, while compound 17 achieved the strongest binding affinity. Furthermore, in
silico ADME predictions for the most active molecules showed
good pharmacokinetic profiles and drug-likeness. Consequently, the
results suggested that semicarbazone-sulfonate hybrid compounds 12, 17, and 18 were promising potential
multifunctional agents targeting cholinergic dysfunction in Alzheimer’s
disease (AD).