7-amino-3,4-dihydro-1h-quinolin-2-one, a compound similar to the substituted coumarins, inhibits alpha-carbonic anhydrases without hydrolysis of the lactam ring

Abstract

7-Amino-3,4-dihydro-1H-quinolin-2-one, a compound structurally similar to coumarins, recently discovered class of inhibitors of the alpha-carbonic anhydrases (CAs, EC 4.2.1.1) was investigated for its interaction with all human (h) CA isoforms, hCA I-XIV. The compound was not an inhibitor of the cytosolic, widespread isoform hCA II (K-I > 10 mu M), was a weak inhibitor of hCA I, III, IV, VA, VI and XIII (K(I)s in the range of 0.90-9.5 mu M) but effectively inhibited the cytosolic isoform hCA VII (K-I of 480 nM) as well as the transmembrane isoforms hCA IX, XII and XIV (K(I)s in the range of 16.1-510 nM). Against many CA isoforms this lactam was a better inhibitor compared to the structurally similar 4-methyl-7-aminocoumarin, but unlike this compound, the lactam ring was not hydrolyzed and the inhibition was due to the intact bicyclic amino-quinolinone scaffold. Bicyclic lactams strucurally related to coumarins are thus a new class of CA inhibitors possessing however a distinct inhibition mechanism compared to the coumarins which undergo a hydrolysis of their lactone ring for generating the enzyme inhibitory species.