title: Discovery and structure-activity relationship of novel 2,3-dihydrobenzofuran-7-carboxamide and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide derivatives as poly(ADP-ribose)polymerase-1 inhibitors.
abstract: Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3',4'-dihydroxybenzylidene 58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4'-hydroxyl/4'-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66-68, 70, 72, and 73; IC50 values from 0.718 to 0.079 μM). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (-)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University , Queens, New York 11439, United States.
authors.forename: Maulik R
authors.initials: MR
authors.lastname: Patel
authors.forename: Aaditya
authors.initials: A
authors.lastname: Bhatt
authors.forename: Jamin D
authors.initials: JD
authors.lastname: Steffen
authors.forename: Adel
authors.initials: A
authors.lastname: Chergui
authors.forename: Junko
authors.initials: J
authors.lastname: Murai
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: John M
authors.initials: JM
authors.lastname: Pascal
authors.forename: Louis D
authors.initials: LD
authors.lastname: Trombetta
authors.forename: Frank R
authors.initials: FR
authors.lastname: Fronczek
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D002645:Chickens; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001572:Benzofurans; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C043168:coumaran