Studies on N-hydroxyguanidine derivatives, potential nitric oxide donor drugs

Abstract

The ability of substituted N-hydroxyguanidines to act as nitric oxide donor drugs has been previously established. To further investigate the potential of this class of compound as nitric donor drugs a number of new N-hydroxyguanidines were prepared. The compounds were synthesised and then subjected to a number of chemical and biological tests. A number of the examples prepared were indeed shown to be oxidised under chemical conditions to give nitric oxide. The nitric oxide was tested for using the Greiss test. One example, 1-benzyl-1-methyl-2-hydroxyguanidine showed biological activity and was found to be a vasodilator. In addition an X-ray crystal structure of this compound was obtained which gave a further insight into the conformation of this type compound and related analogues. A number of ureas were also prepared for use in the biological and chemical testing. Under chemical conditions the ureas were not oxidised thus indicating that the hydroxyguanidine functionality was required for nitric oxide generation. O-Substituted N-hydroxyguanidines were also prepared in an effort to examine the possibility of selectively targeting the molecule to the site of action for nitric oxide release. These compounds were found to produce a small amount of nitric oxide under chemical oxidation, therefore confirming their potential as potential nitric oxide donor compounds. Acid catalysed decomposition of O-THP-1,1,-dibenzyl-2- hydroxyguanidine was studied. The reaction was carried out at various pHs and was monitored using HPLC. It was found that the THP protecting group could be removed to give the free N-hydroxyguanidine. More easily removed O-substituents are probably required to produce successful prodrugs. However the reaction only gave a reasonable rate at a very low pH (t1/2 = 122 s at pH 0). A number of O-substituted hydroxylamines were then prepared in an attempt to increase the range of O-substituted N-hydroxyguanidines that could be obtained.