SYNTHESIS, COMPUTATIONAL STUDY, IN VITRO AND IN VIVO ANTICHOLINESTERASE PROPERTIES OF GLYCINE DERIVED DIPEPTIDE BEARING SULPHONAMIDE CARBOXAMIDE SCAFFOLDS
JOY NKECHI ORJI1,2, SOLOMON IZUCHI ATTAH1*, UCHECHUKWU CHRIS OKORO1, RAFAT ALI THOMAS2, NKPABO OGBIJI1, COSMAS CHINWEIKE EZE3, DAVID IZUCHUKWU UGWU1, FLORENCE UCHECHUKWU EZE1, BENJAMIN EBELE EZEMA1, FIDELIA NGOZI IBEANU3, VIVIAM IFEOMAE OKONKWO5, BENJAMIN ONYEBUCHI EZEMA4
1 Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka, Nigeria.
2 Department of Chemistry, Indian Institute of Technology, Kanpur, India.
3 Natural Science Unit, University of Nigeria, Nsukka, Nigeria.
4 Biochemistry Unit, Department of Science Laboratory Technology, University of Nigeria, Nsukka, Nigeria.
5 Chemistry Unit, Department of Science Laboratory Technology, University of Nigeria, Nsukka, Nigeria.
Afr. J Pharm Res Dev; Volume 18(2): 841-850; 2026
ABSTRACT
Cholinesterase is one of several key enzymes required for the normal functioning of the human neurological system. Acetylcholine is an organic compound (ester of acetic acid and choline) that functions in the brain and body of many animals. It is a neurotransmitter that plays a major role in memory, learning and involuntary muscle movements. Its primary role is to transmit signals between the central nervous system (CNS) and the peripheral nervous system (PNS). Insufficient levels of acetylcholine are associated with conditions such as Alzheimer’s disease (AD), Parkinson’s disease and myasthenia (muscle weakness). This study investigates the anti-cholinesterase activity of five newly synthesized glycine-derived dipeptides bearing sulphonamide and carboxamide functionalities. The nucleophilic substitution reaction of L-threonine and benzenesulphonyl chloride gave the sulphonamide derivative. The reaction of L-threonine sulphonamide with deprotected carboxamide derivatives gave the target products. Structural elucidation was performed using spectroscopic techniques (FT-IR, 1H-NMR, 13C-NMR and HR-MS). In vitro and ex vivo anti-cholinesterase evaluation was done with rat brains. Compound 8e had the highest percentage inhibition of 47.91% (IC50 = 8.91 mg/mL) for acetylcholinesterase (AChE) and compound 8c, 40.08% (IC50 = 28.11 mg/mL) for butyrylcholinesterase (BuChE), respectively. This is moderately comparable to the standard drug, galanthamine with a percentage inhibition of 82.02 ± 2.87%. The computational and physicochemical studies revealed compound 8c having the highest binding energy of -11.0 kcal/mol for AChE and compound 8d exhibited the highest binding energy of -10.9 kcal/mol for BuChE. The result of this study showed that the newly synthesized compounds would not pose oral bioavailability, transport and permeability problems from the computational analysis. Due to the effective inhibitory biological properties of compounds 8e and 8c against AChE and BuChE, the two hit compounds are expected to serve as a promising therapy for Alzheimer’s disease.
Keywords: Acetylcholine, Alzheimer’s disease, sulphonamides, acetylcholinesterase, butyrylcholinesterase, ex vivo study, computational study.
Correspondence: [email protected]
DOI: https://doi.org/10.59493/ajopred/2026.2.12 | ISSN: 0794-800X (print); 1596-2431 (online)