Design,synthesis and evaluation of novel 2-hydroxypyrrolobenzodiazepine-5,11-dione analogues as potent angiotensin converting enzyme (ACE) inhibitors |
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| Authors: | Dinesh Addla Anvesh Jallapally Abhinav Kanwal Balasubramanian Sridhar Sanjay K Banerjee Srinivas Kantevari |
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| Institution: | 1. CPC Division (Organic Chemistry Division-II), CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India;2. Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India;3. Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 607, India |
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| 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-benzoe]pyrrolo1,2-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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| Keywords: | ACE Inhibitors Benzodiazepines Hypertension Molecular hybridization Proline |
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