The anti-Alzheimer potential of novel spiroindolin-1,2-diazepine derivatives as targeted cholinesterase inhibitors with modified substituents.

Autor: Pourtaher H; Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr, 75169, Iran., Hasaninejad A; Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr, 75169, Iran. alirezahasaninejad@gmail.com., Zare S; Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran., Tanideh N; Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran., Iraji A; Research Center for Traditional Medicine and History of Medicine, Department of Persian Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. aida.iraji@gmail.com.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Jul 24; Vol. 13 (1), pp. 11952. Date of Electronic Publication: 2023 Jul 24.
DOI: 10.1038/s41598-023-38236-0
Abstrakt: In this study, a new series of spiro indolin-1,2-diazepine were designed, synthesized, and screened for their cholinesterase inhibitory activities. A novel, green, high-yielding approach was constructed to synthesize spiro indolin-1,2-diazepine derivatives through a cascade reaction of different isatins, malononitrile and 1,1-enediamines (EDAMs) via sequential four-component reactions to produce the target compounds with good to excellent yields. Next the inhibitory potencies of all derivatives were determined spectroscopically at 415 nm using the modified Ellman method. The results of the in vitro screening indicated that 5l with spiroindolin-1,2-diazepine core bearing 5-NO 2 at R 1 and 4-OH at R 2 was the most potent and selective AChE inhibitor with an IC 50 value of 3.98 ± 1.07 µM with no significant inhibition against BChE while 5j was the most active analog against both AChE and BChE enzymes. The structure-activity relationships suggested the variation in the inhibitory activities of derivatives was affected by different substitutions on the indolinone ring as well as the phenyl moiety. The enzyme kinetic studies of the most potent compound 5l at five different concentrations and acetylthiocholine substrate (0.1-1 mM) by Ellman's method revealed that it inhibited AChE in a mixed mode with a K i of 0.044 μM. A molecular docking study was performed via induced fit docking protocol to predict the putative binding interaction. It was shown that the moieties used in the initial structure design play a fundamental role in interacting with the enzyme's binding site. Further, molecular dynamics simulations with the Schrödinger package were performed for 5l in a complex with AChE and revealed that compound 5l formed the stable complex with the enzyme. The MTT toxicity assessments against the neuroblastoma cell line were executed, and no toxicity was seen for 5l under the tested concentrations.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje