Design and development of 1,3,4-oxadiazole derivatives as potential inhibitors of acetylcholinesterase to ameliorate scopolamine-induced cognitive dysfunctions |
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| Institution: | 1. Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi 221 005, India;2. Department of Pharmaceutical Sciences, Assam University, Silchar 788 011, India;3. National Toxicology Centre, Vadgaon Khurd, Sinhagad Road, Pune 411 041, India;1. National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China;2. Department of Pharmacy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, PR China;3. School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China;4. Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, PR China;5. College of Chemistry & Pharmacy, Northwest A&F University, Yangling, PR China;1. Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka 142432, Russia;2. Emanuel Institute of Biochemical Physics Russian Academy of Sciences, Moscow 119334, Russia;3. Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia;4. I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119881, Russia;5. Biomedical Research Centre, University Hospital Hradec Kralove, 500 05 Hradec Kralove, Czech Republic;6. Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109 USA;7. Department of Neurology, University of Michigan, Ann Arbor, MI 48109 USA;8. Center of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109 USA |
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| Abstract: | The novel hybrids bearing 4-aminopyridine (4-AP) tethered with substituted 1,3,4-oxadiazole nucleus were designed, synthesized, and evaluated for their potential AChE inhibitory property along with significant antioxidant potential. The inhibitory potential (IC50) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman’s method. Among all the compounds, 9 with 4-hydroxyl substituent showed maximum hAChE inhibition with the non-competitive type of enzyme inhibition (IC50 = 1.098 µM; Ki = 0.960 µM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed significant BBB permeability in most of the synthesized compounds. Meanwhile, compound 9 also inhibited AChE-induced Aβ aggregation (38.2–65.9%) by thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 9. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 9 in brain homogenates. |
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| Keywords: | Acetylcholinesterase Butyrylcholinesterase 1 3 4-Oxadiazole Molecular hybridization 4-Aminopyridine |
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