Quinazolinones, Quinazolinthiones, and Quinazolinimines as Nitric Oxide Synthase Inhibitors: Synthetic Study and Biological Evaluation

The synthesis of different compounds with a quinazolinone, quinazolinthione, or quinazolinimine skeleton and their in vitro biological evaluation as inhibitors of inducible and neuronal nitric oxide synthase (iNOS and nNOS) isoforms are described. These derivatives were obtained from substituted 2‐aminobenzylamines, using diverse cyclization procedures. Furthermore, the diamines were synthesized by two routes: A conventional pathway and an efficient one‐pot synthesis in a continuous‐flow hydrogenator. The structures of these heterocycles were confirmed by 1H and 13C nuclear magnetic resonance and high‐resolution mass spectroscopy data. The structure–activity relationships of the target molecules are discussed in terms of the effects of both the R radical and the X heteroatom in the 2‐position. In general, the assayed compounds behave as better iNOS than nNOS inhibitors, with the quinazolinone 11e being the most active inhibitor of all tested compounds and the most iNOS/nNOS selective one. Different compounds with a quinazolinone, quinazolinthione, or quinazolinimine skeleton were synthesized by diverse cyclization procedures from substituted 2‐aminobenzylamines, and evaluated as in vitro inhibitors of the inducible and neuronal nitric oxide synthase (iNOS and nNOS) isoforms. The structure–activity relationships are discussed in terms of the effects of both the R radical and the X heteroatom in the 2‐position.