طراحی و سنتز مشتقات جدید 3و5-بیس-N-(آریل/هتروآریل) کارباموئیل-4-آریل-1و4-دی هیدروپیریدین به عنوان مهارکنندگان کوچک مولکول آنزیم بتا-سکرتاز

رزاقی اصل, نیما and فیروزی, امیدرضا and همتی نژاد, بهرام and جاویدنیا, کتایون and ادراکی, نجمه and میری, رامین (1392) طراحی و سنتز مشتقات جدید 3و5-بیس-N-(آریل/هتروآریل) کارباموئیل-4-آریل-1و4-دی هیدروپیریدین به عنوان مهارکنندگان کوچک مولکول آنزیم بتا-سکرتاز. Bioorganic and Medicinal Chemistry ــ 21 (22). pp. 6893-6909. شاپا 0968-0896

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Official URL: http://www.sciencedirect.com/science/article/pii/S...


Design and synthesis of novel 3,5-bis-N-(aryl/heteroaryl carbamoyl-4-aryl-1,4-dihydropyridines as small molecule BACE-1 inhibitors

English Abstract

Alzheimer disease (AD) is a neuronal dementia for which no treatment has been consolidated yet. Major pathologic hallmark of AD is the aggregated extracellular amyloid-β plaques in the brains of disease sufferers. Aβ-peptide is a major component of amyloid plaques and is produced from amyloid precursor protein (APP) via the proteolysis action. An aspartyl protease known as β-site amyloid precursor protein cleaving enzyme (BACE-1) is responsible for this proteolytic action. Distinctive role of BACE-1 in AD pathogenesis has made it a validated target to develop anti-Alzheimer agents. Our structure-based virtual screening method led to the synthesis of novel 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridine BACE-1 inhibitors (6a–6p; in vitro hits). Molecular docking and DFT-based ab initio studies using B3LYP functional in association with triple-ζ basis set (TZV) proposed binding mode and binding energies of ligands in the active site of the receptor. In vitro BACE-1 inhibitory activities were determined by enzymatic fluorescence resonance energy transfer (FRET) assay. Most of the synthesized dihydropyridine scaffolds were active against BACE-1 while 6d, 6k, 6n and 6a were found to be the most potent molecules with IC50 values of 4.21, 4.27, 4.66 and 6.78 μM, respectively. Superior BACE-1 inhibitory activities were observed for dihydropyridine derivatives containing fused/nonfused thiazole containing groups, possibly attributing to the additional interactions with S2–S3 subpocket residues. Relatively reliable correlation between calculated binding energies and experimental BACE-1 inhibitory activities was achieved (R2 = 0.51). Moreover, compounds 6d, 6k, 6n and 6a exhibited relatively no calcium channel blocking activity with regard to nifedipine suggesting them as appropriate candidates for further modification(s) to BACE-1 inhibitory scaffolds.

Item Type:Article
زبان سند : انگلیسی
نویسنده اول :نیما رزاقی اصل
نویسنده :امیدرضا فیروزی
نویسنده :بهرام همتی نژاد
نویسنده :کتایون جاویدنیا
نویسنده :نجمه ادراکی
نویسنده مسئول :رامین میری
Additional Information:Impact Factor: 2.903 Abstracting and Indexing: Science Citation Index , Scopus , BIOSIS , Beilstein Database , Biochemistry and Biophysics Citation Index , Cancerlit , Chemical Abstracts , Chemical Citation Index , Current Contents , Current Contents/Life Sciences , MEDLINE , EMBASE , Pascal , Research Alert , SCISEARCH , Excerpta Medica , Elsevier BIOBASE/Current Awareness in Biological Sciences , TOXFILE
Uncontrolled Keywords:آلزایمر ، بتاسکرتاز ، دی هیدروپیریدین ، غربالگری مجازی
کلیدواژه ها (انگلیسی):Alzheimer , BACE-1 , Dihydropyridine , Virtual screening
Subjects:QV pharmacology > QV 744 Medicinal Chemistry
Divisions:School of Pharmacy > Department of Medicinal Chemistry
ID Code:5397
Deposited By: Dr Nima Razzaghi-Asl
Deposited On:14 Dec 1392 14:17
Last Modified:14 Dec 1392 14:17

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