期刊
JOURNAL OF MOLECULAR STRUCTURE
卷 1262, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.molstruc.2022.132979
关键词
Alzheimer?s disease; Acetylcholinesterase; B -secretase; Propamidine; Virtual screening; MD simulation
The use of multifunctional agents is crucial in managing neurodegenerative disorders. This study identified potential drugs with dual targeting effects and performed further analysis and testing.
The use of multifunctional agents could act as a crucial strategy in the management of neurodegenerative disorders like Alzheimer's disease (AD). In search of multitargeted directed ligands for the treatment of AD, a drug repositioning study has been performed using In silico tools. Virtual screening of a library (Drug Central Database) containing 4199 FDA-approved drugs was utilized for the purpose, and denopamine, guanethidine, and propamidine were identified as hits to target both acetylcholinesterase (AChE) and ,B-secretase (BACE-1). Further, MM/GBSA and MD simulation analysis was also performed which suggested that propamidine, an antibacterial and antifungal drug , may become a crucial pharmacophore to design multi-target directed ligands for AD therapy. Finally, a series of structurally modified derivatives of propamidine by replacement of terminal amidines with substituted benzamide and acetamide moiety on both ends were synthesized, characterized, and tested for their anti-AD action. Compound 27 of the structurally modified series of propamidine has shown significant in vitro hAChE and hBACE-1 inhibition at submicromolar concentration range (hAChE: IC 50 = 0.832 +/- 0.05 }IM and hBACE-1: IC 50 = 0.428 +/- 0.036 }IM). Compounds 27 has also shown significant propidium iodide displacement from the PAS binding region and exhibited good self and AChE-induced Amyloid- ,B (A ,B) aggregation inhibition in thioflavin T assay. The in-vivo behavioral studies of compound 27 displayed significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. (c) 2022 Elsevier B.V. All rights reserved.
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