Title : Design, synthesis, biological evaluation, and docking study of novel dual-acting thiazole-pyridiniums inhibiting acetylcholinesterase and beta-amyloid aggregation for Alzheimer's disease - Ghotbi_2020_Bioorg.Chem_103_104186 |
Author(s) : Ghotbi G , Mahdavi M , Najafi Z , Moghadam FH , Hamzeh-Mivehroud M , Davaran S , Dastmalchi S |
Ref : Bioorg Chem , 103 :104186 , 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 beta-amyloid aggregation (Abeta) was evaluated. Compounds 7d and 7j showed the best AChE inhibitory activities at the submicromolar concentration range (IC(50) values of 0.40 and 0.69 muM, 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 beta-amyloid self-aggregation inhibitory effects (20.38 and 42.66% respectively) stronger than donepezil (14.70%) assayed at 10 muM concentration. Moreover, compounds 7j and 7m were shown to be effective neuroprotective agents in H(2)O(2)-induced oxidative stress on PC(12) 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. |
PubMedSearch : Ghotbi_2020_Bioorg.Chem_103_104186 |
PubMedID: 32890993 |
Ghotbi G, Mahdavi M, Najafi Z, Moghadam FH, Hamzeh-Mivehroud M, Davaran S, Dastmalchi S (2020)
Design, synthesis, biological evaluation, and docking study of novel dual-acting thiazole-pyridiniums inhibiting acetylcholinesterase and beta-amyloid aggregation for Alzheimer's disease
Bioorg Chem
103 :104186
Ghotbi G, Mahdavi M, Najafi Z, Moghadam FH, Hamzeh-Mivehroud M, Davaran S, Dastmalchi S (2020)
Bioorg Chem
103 :104186