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 (1) H and (13) C 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.
Facultad de Farmacia, Departamento de Química Farmacéutica y Orgánica, Universidad de Granada, Granada, Spain.
M Encarnación
ME
Camacho
Facultad de Farmacia, Departamento de Química Farmacéutica y Orgánica, Universidad de Granada, Granada, Spain.
Mariem
M
Chayah
Facultad de Farmacia, Departamento de Química Farmacéutica y Orgánica, Universidad de Granada, Granada, Spain.
M Esther
ME
García
Facultad de Farmacia, Departamento de Química Farmacéutica y Orgánica, Universidad de Granada, Granada, Spain.
Nerea
N
Fernández-Sáez
Facultad de Farmacia, Departamento de Química Farmacéutica y Orgánica, Universidad de Granada, Granada, Spain.
Fabio
F
Arias
Facultad de Farmacia, Departamento de Química Farmacéutica y Orgánica, Universidad de Granada, Granada, Spain.
Miguel A
MA
Gallo
Facultad de Farmacia, Departamento de Química Farmacéutica y Orgánica, Universidad de Granada, Granada, Spain.
M Dora
MD
Carrión
D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D011799:Quinazolines; D052999:Quinazolinones; D013871:Thiones; C000614528:quinazolinimine; C000614529:quinazolinthione; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II
Inhibitors; Quinazoline; Synthesis