Design, synthesis, and evaluation in vitro of quinoline-8-carboxamides, a new class of poly(adenosine-diphosphate-ribose)polymerase-1 (PARP-1) inhibitor

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Abstract

Poly(ADP-ribose)polymerase-1 is an important target enzyme in drug design; inhibitors have a wide variety of therapeutic activities. A series of quinoline-8-carboxamides was designed to maintain the required pharmacophore conformation through an intramolecular hydrogen bond. 3-Substituted quinoline-8-carboxamides were synthesized by Pd-catalyzed couplings (Suzuki, Sonogashira, Stille) to 3-iodoquinoline-8-carboxamide, an efficient process that introduces diversity in the final step. 2-Substituted quinoline-8-carboxamides were prepared by selective Pd-catalyzed couplings at the 2-position of 2,8-dibromoquinoline, followed by lithium−bromine exchange of the intermediate 2-(alkyl/aryl)-8-bromoquinolines and reaction with trimethylsilyl isocyanate. The intramolecular hydrogen bond was confirmed by X-ray and by NMR. The SAR of the 3-substituted compounds for inhibition of human recombinant PARP-1 activity showed a requirement for a small narrow group. Substituents in the 2-position increased potency, with the most active 2-methylquinoline-8-carboxamide having IC50 = 500 nM (IC50 = 1.8 μM for 5-aminoisoquinolin-1-one (5-AIQ, a standard water-soluble inhibitor)).
Original languageEnglish
Pages (from-to)868-877
Number of pages10
JournalJournal of Medicinal Chemistry
Volume52
Issue number3
Early online date31 Dec 2008
DOIs
Publication statusPublished - 12 Feb 2009

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