Design, synthesis and evaluation of novel 2-hydroxypyrrolobenzodiazepine-5,11-dione analogues as potent angiotensin converting enzyme (ACE) inhibitors

被引：12

作者：

Addla, Dinesh ^{[1
]}

Jallapally, Anvesh ^{[1
,2
]}

Kanwal, Abhinav ^{[2
]}

Sridhar, Balasubramanian ^{[3
]}

Banerjee, Sanjay K. ^{[2
]}

Kantevari, Srinivas ^{[1
]}

机构：

[1] CSIR Indian Inst Chem Technol, CPC Div, Organ Chem Div 2, Hyderabad 500607, Andhra Pradesh, India

[2] CSIR Indian Inst Chem Technol, Med Chem & Pharmacol Div, Hyderabad 500607, Andhra Pradesh, India

[3] CSIR Indian Inst Chem Technol, Lab Xray Crystallog, Hyderabad 500607, Andhra Pradesh, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 15期

关键词：

ACE Inhibitors; Benzodiazepines; Hypertension; Molecular hybridization; Proline; BINDING; LIBRARY; SCAFFOLD;

D O I：

10.1016/j.bmc.2013.05.031

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of novel 10-substituted 2-hydroxypyrrolobenzodiazepine-5,11-diones designed through structure based rational hybridization approach, synthesized by the cyclodehydration of isotonic anhydride with (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid followed by N-substitution, were evaluated as angiotensin converting enzyme (ACE) inhibitors. Among all the new compounds screened (2R, 11aS)-10-((4-bromothiophen-2-yl)methyl)-2-hydroxy-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11 (10H,11aH)dione, 5v (IC50: 0.272 mu M) emerged as most active non-carboxylic acid ACE inhibitor with minimal toxicity comparable to clinical drugs Lisinopril, Benazepril and Ramipril. Favorable binding characteristics in docking studies also supported the experimental results. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：4485 / 4493

页数：9

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