Design, synthesis, in vitro, and in vivo evaluation of novel phthalazinone-based derivatives as promising acetylcholinesterase inhibitors for treatment of Alzheimer's disease.

Autor: Ezzat MAF; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt., Abdelhamid SM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt., Fouad MA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.; Pharmaceutical Chemistry Department, School of Pharmacy, Newgiza University, Cairo, Egypt., Abdel-Aziz HA; Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, Egypt., Allam HA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Jazyk: angličtina
Zdroj: Drug development research [Drug Dev Res] 2023 Sep; Vol. 84 (6), pp. 1231-1246. Date of Electronic Publication: 2023 May 26.
DOI: 10.1002/ddr.22082
Abstrakt: Twenty novel phthalazinone-based compounds were designed as acetylcholinesterase (hAChE) inhibitors. Compounds 7e and 17c demonstrated comparable or superior activity compared to donepezil, respectively, in in vitro enzyme assay. Moreover, both compounds 7e and 17c possess minimal toxicity on hepatic and neuroblastoma cell lines. Besides, it was proved that compounds 7e and 17c have percentage alternations and a transfer latency time comparable to donepezil and can alleviate the cognitive impairment caused by the scopolamine-induced model in mice. The kinetic analysis for compound 17c suggested this compound as a mixed-type inhibitor that could bind to both the peripheral (PAS) and the catalytic site (CAS) of the hAChE enzyme. The synthesized molecules were subjected to in silico analyses, including molecular docking studies, and the outcomes were consistent with the in vitro findings.
(© 2023 Wiley Periodicals LLC.)
Databáze: MEDLINE
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