N-Aryl N'-hydroxyguanidines, a new class of NO-donors after selective oxidation by nitric oxide synthases: structure-activity relationship.

The formation of nitric oxide (NO) was followed during the oxidation of 37 N-hydroxyguanidines or related derivatives, including 18 new N-aryl N‘-hydroxyguanidines, by recombinant inducible nitric oxide synthase (NOS II). Several N-aryl N‘-hydroxyguanidines bearing a relatively small, electron-donating para subtituent, such as H, F, Cl, CH3, OH, OCH3, and NH2, led to NO formation rates between 8 and 41% of that of NO formation from the natural NOS substrate, Nω-hydroxy-l-arginine (NOHA). The characteristics of these reactions were very similar to those previously reported for the oxidation of NOHA by NOS:  (i) the strict requirement of NOS containing (6R)-5,6,7,8-tetrahydro-l-biopterin, reduced nicotinamide adenine dinucleotide phosphate, and O2 for the oxidation to occur, (ii) the formation of NO and the corresponding urea in a 1:1 molar ratio, and (iii) a strong inhibitory effect of the classical NOS inhibitors such as Nω-nitro-l-arginine and S-ethyl-iso-thiourea. Structure−activity relationship studies...