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.
authors.affiliation: CPC Division (Organic Chemistry Division-II), CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Addla
authors.forename: Anvesh
authors.initials: A
authors.lastname: Jallapally
authors.forename: Abhinav
authors.initials: A
authors.lastname: Kanwal
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Sridhar
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Banerjee
authors.forename: Srinivas
authors.initials: S
authors.lastname: Kantevari
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D011758:Pyrroles; D001569:Benzodiazepines