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

Dinesh Addla; Anvesh Jallapally; Abhinav Kanwal; Balasubramanian Sridhar; Sanjay K. Banerjee; Srinivas Kantevari

doi:10.1016/j.bmc.2013.05.031

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

Dinesh Addla, Anvesh Jallapally, Abhinav Kanwal, Balasubramanian Sridhar, Sanjay K. Banerjee, Srinivas Kantevari

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

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 μM) 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.

Original language	English
Pages (from-to)	4485-4493
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	21
Issue number	15
DOIs	https://doi.org/10.1016/j.bmc.2013.05.031
Publication status	Published - 01-08-2013

All Science Journal Classification (ASJC) codes

Pharmaceutical Science
Drug Discovery
Organic Chemistry
Molecular Medicine
Molecular Biology
Clinical Biochemistry
Biochemistry

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10.1016/j.bmc.2013.05.031

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

abstract = "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 μM) 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.",

author = "Dinesh Addla and Anvesh Jallapally and Abhinav Kanwal and Balasubramanian Sridhar and Banerjee, {Sanjay K.} and Srinivas Kantevari",

year = "2013",

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doi = "10.1016/j.bmc.2013.05.031",

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AU - Addla, Dinesh

AU - Jallapally, Anvesh

AU - Kanwal, Abhinav

AU - Sridhar, Balasubramanian

AU - Banerjee, Sanjay K.

AU - Kantevari, Srinivas

PY - 2013/8/1

Y1 - 2013/8/1

N2 - 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 μM) 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.

AB - 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 μM) 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.

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

Abstract

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