Amidine-Based Compounds Affecting L-Arginine Metabolism

The l-Arg availability or the production of end products can be altered in different pathological conditions, resulting in profound physiologic consequences, with disruption of normal homeostasis in the human body. In particular, in recent years great interest has been directed to therapeutic applications able to restore the metabolism of l-Arg, increasing substrate availability or influencing specific pathways. The development of arginine mimetics is one of the approaches used for treating diseases related to the altered metabolism of l-Arg; main l-Arg structural modifications refer to the α-N or α-C derivatization, the synthesis of constrained analogs, or the diversification of the guanidino moiety with a bioisostere. Among arginine mimetics, the amidino motif has proved to be the most important substitute of the guanidine architecture. In effect, amidines are derivatives of carboxylic acids, in which the hydroxyl group is replaced by an amino group and the carbonyl group by an azomethine double bond. They are strong organic bases due to the charge delocalization occurring over the two nitrogen atoms in the protonated form. This structure offers the possibility to establish specific interactions, mainly bidentate hydrogen bondings, with proteins, and the nature of the amidino substituent can modulate the structural protein recognition process