Development of Urea and Thiourea Kynurenamine Derivatives: Synthesis, Molecular Modeling, and Biological Evaluation as Nitric Oxide Synthase Inhibitors

Herein we describe the synthesis of a new family of kynurenamine derivatives with a urea or thiourea moiety, together with their in vitro biological evaluation as inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS, respectively), enzymes responsible for the biogenesis of NO. These compounds were synthesized from a 5-substituted-2-nitrophenyl vinyl ketone scaffold in a five-step procedure with moderate to high chemical yields. In general, the assayed compounds show greater inhibition of iNOS than of nNOS, with 1-[3-(2-amino-5-chlorophenyl)-3-oxopropyl]-3-ethylurea (compound 5n) being the most potent iNOS inhibitor in the series and the most iNOS/nNOS-selective compound. In this regard, we performed molecular modeling studies to propose a binding mode for this family of compounds to both enzymes and, thereby, to elucidate the differential molecular features that could explain the observed selectivity between iNOS and nNOS.