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Design, Synthesis, Biological Evaluation, and Docking Study of Novel Dual-Acting Thiazole-Pyridiniums Inhibiting Acetylcholinesterase and Β-Amyloid Aggregation for Alzheimer's Disease Publisher Pubmed



Ghotbi G1, 2, 3 ; Mahdavi M4 ; Najafi Z5 ; Moghadam FH6 ; Hamzehmivehroud M2, 3 ; Davaran S3, 7 ; Dastmalchi S2, 3, 8
Authors
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Authors Affiliations
  1. 1. Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  2. 2. Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  3. 3. Department of Medicinal Chemistry, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
  4. 4. Endocrinology & Metabolism Research Institute (EMRI), Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
  6. 6. Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
  7. 7. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  8. 8. Faculty of Pharmacy, Near East University, POBOX:99138, Nicosia, North Cyprus, Mersin 10, Turkey

Source: Bioorganic Chemistry Published:2020


Abstract

New compounds containing thiazole and pyridinium moieties were designed and synthesized. The potency of the synthesized compounds as selective inhibitors of acetylcholinesterase (AChE), and β-amyloid aggregation (Aβ) was evaluated. Compounds 7d and 7j showed the best AChE inhibitory activities at the submicromolar concentration range (IC50 values of 0.40 and 0.69 μM, respectively). Most of the novel compounds showed moderate to low inhibition of butyrylcholinesterase (BChE), which is indicative of their selective inhibitory effects towards AChE. Kinetic studies using the most potent compounds 7d and 7j confirmed a mixed-type of AChE inhibition mechanism in accordance with the docking results, which shows their interactions with both catalytic active (CAS) and peripheral anionic (PAS) sites. The specific binding of 7a, 7j, and 7m to PAS domain of AChE was also confirmed experimentally. In addition, 7d and 7j were able to show β-amyloid self-aggregation inhibitory effects (20.38 and 42.66% respectively) stronger than donepezil (14.70%) assayed at 10 μM concentration. Moreover, compounds 7j and 7m were shown to be effective neuroprotective agents in H2O2-induced oxidative stress on PC12 cells almost similar to those observed for donepezil. The ability of 7j to pass blood-brain barrier was demonstrated using the PAMPA method. The results presented in this work provide useful information about designing novel anti-Alzheimer agents. © 2020 Elsevier Inc.
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