مهار آنزیم بتا-سکرتاز آلزایمر توسط مشتقات 2و6-دی آلکیل-4-کرومن-3-ایل-1و4-دی هیدروپیریدین-3و5-دی کربوسیلات

رزاقی اصل, نیما and نِها, آگاروال and اسمریتی, اسریواستاوا and ویریندر, پارمار and آشوک, پراساد and رامین, میری and لوسیانو, ساسو and امیدرضا, فیروزی (1394) مهار آنزیم بتا-سکرتاز آلزایمر توسط مشتقات 2و6-دی آلکیل-4-کرومن-3-ایل-1و4-دی هیدروپیریدین-3و5-دی کربوسیلات. Medicinal Chemistry Research ــ 24 (8). pp. 3230-3241. شاپا 2523-1054

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Official URL: http://link.springer.com/article/10.1007%2Fs00044-...


Inhibition of Alzheimer’s BACE-1 by 2,6-dialkyl-4-chromon-3-yl- 1,4-dihydropyridine-3,5-dicarboxylates

English Abstract

Alzheimer’s disease is the most common cause of dementia in the elderly, and no disease-modifying therapy is yet available for this devastating pathology. Deposition of different physicochemical forms of amyloid-b peptides is a critical phase in the pathogenesis of Alzheimer’s disease. b-Site amyloid precursor protein cleaving enzyme 1 (BACE- 1) is a major enzyme responsible for amyloid-b production; therefore, inhibition of this enzyme represents a promising approach for the discovery of amyloid-b-lowering agents. In this study, a series of novel 2,6-dialkyl-4-chromon-3-yl-1,4- dihydropyridine-3,5-dicarboxylates (14–23) were synthesized and assessed as BACE-1 inhibitors using the Fo¨rster resonance energy transfer-based enzyme assay. Synthesized dihydropyridines exhibited weak-to-relatively-good BACE-1 inhibitory activities. Enzyme inhibitory activities ranged from 6.84 ± 6.62 (23) to 51.32 ± 1.04 (14) percent enzyme inhibitions at the concentration of 10 lM. The structure–activity relationship study showed that the presence of 4-[7- (ethanoyloxy)-4-oxo-4H-chromen-3-yl] moiety at C4 position of dihydropyridine ring (14, 16 and 18) confers higher activity compared with other substitutions at this position. Docking simulation predicted a key H-bond interaction between Asp32 residue and dihydropyridine NH group. Moreover, all docked dihydropyridines made good hydrophobic contacts with S1 and S2 subpockets of BACE-1. A good correlation between estimated binding affinities (pKi) and experimental BACE-1 inhibitory activities at 10 lMwas obtained (R2 = 0.639). The findings of this study suggested that 2,6-dialkyl-4-chromon-3- yl-1,4-dihydropyridine-3,5-dicarboxylates could be promising scaffolds for the discovery of novel BACE-1 inhibitors for management of Alzheimer’s disease.

Item Type:Article
زبان سند : انگلیسی
نویسنده اول :نیما رزاقی اصل
نویسنده :آگاروال نِها
نویسنده :اسریواستاوا اسمریتی
نویسنده :پارمار ویریندر
نویسنده :پراساد آشوک
نویسنده :میری رامین
نویسنده :ساسو لوسیانو
نویسنده مسئول :فیروزی امیدرضا
Additional Information:Impact Factor: (2015) 1.436 Indexed ISI, SCOPUS, EMBASE, Chemical Abstracts Service, Google Scholar, CAB International, Academic OneFile, AGRICOLA, Biological Abstracts, BIOSIS, CAB Abstracts
کلیدواژه ها (انگلیسی):Alzheimer
Subjects:QV pharmacology > QV 744 Medicinal Chemistry
QV pharmacology
Divisions:School of Pharmacy > Department of Medicinal Chemistry
ID Code:5374
Deposited By: Dr Nima Razzaghi-Asl
Deposited On:03 May 1394 05:21
Last Modified:12 Dec 1396 08:22

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