Mono- or di-substituted imidazole derivatives for inhibition of acetylcholine and butyrylcholine esterases |
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| Affiliation: | 1. Pharmaceutical Chemistry Section, Van Yuzuncu Yil University, 65080 Van, Turkey;2. SAFF Chemical Reagent R&D Lab. YYU-TEKNOKENT, 65080 Van, Turkey;3. Department of Chemistry, Atatürk University, 25240 Erzurum, Turkey;4. Department of Medicinal Biology, Van Yuzuncu Yil University, 65080 Van, Turkey;1. Department of Maths and Science Education, Faculty of Education, Kırıkkale University, Yahşihan, 71450, Kırıkkale, Turkey;2. Department of Chemistry, Faculty of Art and Science, Sakarya University, Serdivan, 54187, Sakarya, Turkey;3. Vocational School of Health Services, Cumhuriyet University, 58140, Sivas, Turkey;4. Department of Physics, Faculty of Sciences, Cumhuriyet University, 58140, Sivas, Turkey;5. Department of Physics, Faculty of Sciences, Erciyes University, 38039, Kayseri, Turkey;6. Department of Chemistry, Faculty of Sciences, Ataturk University, 25240, Erzurum, Turkey;1. Department of Chemistry, Faculty of Science, Ataturk University, 25240-Erzurum, Turkey;2. Dogubayazit Ahmed-i Hani Vocational School, Agri Ibrahim Cecen University, 04400-Agri, Turkey;1. Department of Chemistry, Faculty of Arts and Sciences, Inönü University, 44280 Malatya, Turkey;2. Dokuz Eylül University, Faculty of Science, Department of Physics, 35160 Buca, İzmir, Turkey;3. Central Research and Applications Laboratory, Agri Ibrahim Cecen University, 04100 Agri, Turkey;4. Department of Chemistry, Faculty of Sciences, Ataturk University, 25240 Erzurum, Turkey;5. Department of Biotechnology, Faculty of Science, Bartin University, 74100 Bartin, Turkey;6. Department of Pharmacy Services, Nihat Delibalta Göle Vocational High School, Ardahan University, 75700 Ardahan, Turkey;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Selcuk University, Konya, Turkey;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Atatürk University, Erzurum, Turkey;3. Department of Chemistry, Faculty of Science, Atatürk University, Erzurum, Turkey;4. Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, Universita degli Studi di Firenze, Florence, Italy;1. Tercan Vocational High School, Erzincan Binali Yildirim University, Erzincan 24800, Turkey;2. Department of Chemistry, Faculty of Science, Atatürk University, Erzurum 25240, Turkey;3. Department of Pharmaceutical Basic Sciences, Faculty of Pharmacy, Erzincan Binali Yildirim University, Erzincan 24100, Turkey;4. Central Research and Application Laboratory, Agri Ibrahim Cecen University, Agri 04100, Turkey;5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mersin University, Mersin 33169, Turkey;1. Department of Chemistry, College of Science, King Saud University, P.O Box 2455, Riyadh 11451, Saudi Arabia;2. Department of Botany, Davangere University, Shivagangothri, Davangere 577007, Karnataka, India;3. Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Prasanthi Nilayam, A.P. 515 134, India |
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| Abstract: | 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. |
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| Keywords: | SAR Docking Alzheimer’s disease Water solubility ADME Enzyme kinetic study AChE" },{" #name" :" keyword" ," $" :{" id" :" k0040" }," $$" :[{" #name" :" text" ," _" :" acetylcholinesterase BChE" },{" #name" :" keyword" ," $" :{" id" :" k0050" }," $$" :[{" #name" :" text" ," _" :" butyrylcholinesterase ACh" },{" #name" :" keyword" ," $" :{" id" :" k0060" }," $$" :[{" #name" :" text" ," _" :" acetylcholine AD" },{" #name" :" keyword" ," $" :{" id" :" k0070" }," $$" :[{" #name" :" text" ," _" :" Alzheimer’s disease BBB" },{" #name" :" keyword" ," $" :{" id" :" k0080" }," $$" :[{" #name" :" text" ," _" :" blood-brain barrier CAS" },{" #name" :" keyword" ," $" :{" id" :" k0090" }," $$" :[{" #name" :" text" ," _" :" catalytic site ES" },{" #name" :" keyword" ," $" :{" id" :" k0100" }," $$" :[{" #name" :" text" ," _" :" acetyl ester PAS" },{" #name" :" keyword" ," $" :{" id" :" k0110" }," $$" :[{" #name" :" text" ," _" :" peripheral anionic site Log P" },{" #name" :" keyword" ," $" :{" id" :" k0120" }," $$" :[{" #name" :" text" ," _" :" lipophilicity human serum albumin binding WS1" },{" #name" :" keyword" ," $" :{" id" :" k0140" }," $$" :[{" #name" :" text" ," _" :" skin fibroblast cell line SH-SY5Y" },{" #name" :" keyword" ," $" :{" id" :" k0150" }," $$" :[{" #name" :" text" ," _" :" neuroblastoma cell line ADME" },{" #name" :" keyword" ," $" :{" id" :" k0160" }," $$" :[{" #name" :" text" ," _" :" adsorption distribution metabolism excretion |
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