Design, synthesis, and docking analysis of benzene sulfonamide-[1,4]benzoxazepine hybrids as acetylcholinesterase and butyrylcholinesterase inhibitors
4 affiliations
- 1Department of Chemistry, The University of Jordan Amman 11942 Jordan
- 2Department of Chemistry, Mutah University P.O. Box 7 Al-Karak 61710 Jordan
- 3Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University Amman 19392 Jordan
- 4Department of Pharmaceutical Sciences, Zarqa University P.O. Box 13111 Zarqa 2000 Jordan
Abstract
A series of novel hybrid [1,4]benzoxazepine-based sulfonamide derivatives 9–12a–j were synthesized and evaluated for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compounds 9a and 9b exhibited potent dual cholinesterase inhibition, with IC50 values of 9.04 and 8.61 µM against AChE and 3.08 and 4.64 µM against BChE, respectively. Compound 12j emerged as the most potent BChE inhibitor of the series (IC50 = 1.06 ± 0.11 µM), displaying pronounced BChE preference (SI = 10.37), whereas 9d showed the highest BChE selectivity (BChE IC50 = 4.18 ± 0.56 µM; SI = 14.94). Molecular docking studies revealed plausible binding modes of the active compounds within the AChE and BChE active sites, involving π–π stacking, hydrogen bonding, and hydrophobic interactions. The SAR analysis indicated that the effects of nitro and halogen substituents were scaffold- and position-dependent, with selected nitro-substituted derivatives showing enhanced cholinesterase inhibition, whereas brominated analogs exhibited a pronounced preference toward BChE. Integration of the biological and computational data identified compounds 9a, 9b, 9d, 12b, 12j, and 12j as promising candidates for further investigation. Among these, 12j represents the potency lead for BChE inhibition, whereas 9d provides the most pronounced BChE selectivity. ADMET predictions further suggested more favorable physicochemical and pharmacokinetic profiles for selected benzoxazepine-based derivatives, although potential toxicity liabilities were predicted for 12j. Overall, these findings support the [1,4]benzoxazepine–sulfonamide scaffold as a promising starting point for developing BChE-preferring cholinesterase inhibitors.
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BibTeX
@article{habashneh2026design,
title = {{Design, synthesis, and docking analysis of benzene sulfonamide-[1,4]benzoxazepine hybrids as acetylcholinesterase and butyrylcholinesterase inhibitors}},
author = {Almeqdad Y. Habashneh and Muhammad Ashram and Wafa Hourani and Mahmoud A. Al-Sha'er and Murad A. AlDamen},
journal = {RSC Advances},
year = {2026},
month = nov,
doi = {10.1039/d6ra08312a},
url = {https://doi.org/10.1039/d6ra08312a},
note = {CC BY 3.0},
}
RIS
TY - JOUR
TI - Design, synthesis, and docking analysis of benzene sulfonamide-[1,4]benzoxazepine hybrids as acetylcholinesterase and butyrylcholinesterase inhibitors
AU - Almeqdad Y. Habashneh
AU - Muhammad Ashram
AU - Wafa Hourani
AU - Mahmoud A. Al-Sha'er
AU - Murad A. AlDamen
PY - 2026
DA - 2026/11/04
JO - RSC Advances
DO - 10.1039/d6ra08312a
UR - https://doi.org/10.1039/d6ra08312a
AB - A series of novel hybrid [1,4]benzoxazepine-based sulfonamide derivatives 9–12a–j were synthesized and evaluated for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compounds 9a and 9b exhibited potent dual cholinesterase inhibition, with IC50 values of 9.04 and 8.61 µM against AChE and 3.08 and 4.64 µM against BChE, respectively. Compound 12j emerged as the most potent BChE inhibitor of the series (IC50 = 1.06 ± 0.11 µM), displaying pronounced BChE preference (SI = 10.37), whereas 9d showed the highest BChE selectivity (BChE IC50 = 4.18 ± 0.56 µM; SI = 14.94). Molecular docking studies revealed plausible binding modes of the active compounds within the AChE and BChE active sites, involving π–π stacking, hydrogen bonding, and hydrophobic interactions. The SAR analysis indicated that the effects of nitro and halogen substituents were scaffold- and position-dependent, with selected nitro-substituted derivatives showing enhanced cholinesterase inhibition, whereas brominated analogs exhibited a pronounced preference toward BChE. Integration of the biological and computational data identified compounds 9a, 9b, 9d, 12b, 12j, and 12j as promising candidates for further investigation. Among these, 12j represents the potency lead for BChE inhibition, whereas 9d provides the most pronounced BChE selectivity. ADMET predictions further suggested more favorable physicochemical and pharmacokinetic profiles for selected benzoxazepine-based derivatives, although potential toxicity liabilities were predicted for 12j. Overall, these findings support the [1,4]benzoxazepine–sulfonamide scaffold as a promising starting point for developing BChE-preferring cholinesterase inhibitors.
SN - 2046-2069
ER -