Mono- or di-substituted imidazole derivatives for inhibition of acetylcholine and butyrylcholine esterases

• Published in: Bioorganic chemistry Vol. 86; pp. 187 - 196
• Main Authors: Kuzu, Burak, Tan, Meltem, Taslimi, Parham, Gülçin, İlhami, Taşpınar, Mehmet, Menges, Nurettin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-05-2019
• Subjects: Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; ADME; Alzheimer’s disease; Butyrylcholinesterase - chemistry; Butyrylcholinesterase - metabolism; Cell Survival - drug effects; Cells, Cultured; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Docking; Dose-Response Relationship, Drug; Enzyme kinetic study; Fibroblasts - drug effects; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Molecular Docking Simulation; Molecular Structure; SAR; Skin - drug effects; Structure-Activity Relationship; Water solubility; AChE; BChE; SH-SY5Y; AD; BBB; PAS; Alzheimer’s disease; SAR; ADME; ACh; ES; CAS; WS1; Log P; Enzyme kinetic study; Water solubility; Docking; LogKHSA
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.01.044

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•C-2 and C-4 substituted imidazole derivatives were synthesized via a one pot and two steps strategy.•Activity of imidazole derivatives against AChE and BChE were found in a range of nanomolar.•Selectivities, kinetic and docking studies were performed.•Cytotoxicities of selected compound were tested on WS1 and SH-SY5Y whose values are 1790 and 950 µM, respectively.
Mono- or di-substituted imidazole derivatives were synthesized using a one-pot, two-step strategy. All imidazole derivatives were tested for AChE and BChE inhibition and showed nanomolar activity similar to that of the test compound donepezil and higher than that of tacrine. Structure activity relationship studies, docking studies to on X-ray crystal structure of AChE with PDB code 1B41, and adsorption, distribution, metabolism, and excretion (ADME) predictions were performed. The synthesized core skeleton was bound to important regions of the active site of AChE such as the peripheral anionic site (PAS), oxyanion hole (OH), and anionic subsite (AS). Selectivity of the reported test compounds was calculated and enzyme kinetic studies revealed that they behave as competitive inhibitors, while two of the test compounds showed noncompetitive inhibitory behavior. ADME predictions revealed that the synthesized molecules might pass through the blood brain barrier and intestinal epithelial barrier and circulate freely in the blood stream without binding to human serum albumin. While the toxicity of one compound on the WS1 (skin fibroblast) cell line was 1790 µM, its toxicity on the SH-SY5Y (neuroblastoma) cell line was 950 µM.