Design, synthesis, and evaluation in vitro of quinoline-8-carboxamides, a new class of poly(adenosine-diphosphate-ribose)polymerase-1 (PARP-1) inhibitor.
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 IC(50) = 500 nM (IC(50) = 1.8 microM for 5-aminoisoquinolin-1-one (5-AIQ, a standard water-soluble inhibitor)).
Lord
Anna-Marie
AM
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
Mahon
Mary F
MF
Lloyd
Matthew D
MD
Threadgill
Michael D
MD
D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011804:Quinolines; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1