Synthesis, biological activity, and docking studies of novel acetamidines as selective modulators of nitric oxide synthase

Nitric oxide (NO) is an important mediator involved in the regulation of many physiological and pathological processes. [1] The formation of NO is catalyzed by the enzyme nitric oxide synthase (NOS) via the NADPH- and O2-dependent oxidation of L-arginine. Three distinct isoforms of NOS have been identified: the constitutive endothelial (eNOS) and neuronal (nNOS), predominantly expressed in the vascular endothelium and in the nervous system, respectively, and the inducible (iNOS), which generates high levels of NO that modulates inflammation through multiple pathways and plays an important role in the regulation of immune reactions. When highly regulated, the production of NO is beneficial to the host organism. It is, however, believed that a number of disease states arise from excessive or inappropriate production of NO, including cerebral ischemia, septic shock, and arthritis. It has been proposed that overexpression of iNOS contributes to the progression of inflammatory diseases such as rheumatoid arthritis and osteoarthritis. [2] Moreover, there is evidence that also NO overproduction by nNOS plays a key role in these pathologies, and recently published studies reported promising results from chronic inhibition of nNOS as an adjunct therapeutic strategy for motor nerve repair. [3] Selective inhibition of iNOS and nNOS would be a useful therapy for such diseases. [4]. Recently, we have synthesized and evaluated a series of acetamidines structurally related to N-(3-(aminomethyl)benzyl) acetamidine (1400W); among them, compounds characterized by removal of the 3-aminomethyl group and addition of a methyl or an ethyl group on the benzylic carbon connected to the acetamidine nitrogen, showed good inhibitory potencies and high selectivities toward iNOS. [5] Based on the obtained results, other acetamidines and imidazole derivatives were synthesised and biologically evaluated, and a docking study was also performed to shed light on the effects of the structural modifications on the interaction with the NOS.