Bioactive imidamide-based compounds targeted against nitric oxide synthase

• Published in: Bioorganic chemistry Vol. 120; p. 105637
• Main Authors: Arias, Fabio, Franco-Montalban, Francisco, Romero, Miguel, Duarte, Juan, Dora Carrión, M., Encarnación Camacho, M.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.03.2022; Elsevier
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Imidamide; Inducible nitric oxide synthase; Life Sciences & Biomedicine; Neuronal nitric oxide synthase; Nitric oxide synthase inhibitors; Physical Sciences; Science & Technology; Septic shock; Synthesis; Septic shock; Neuronal nitric oxide synthase; Synthesis; Nitric oxide synthase inhibitors; Inducible nitric oxide synthase; Imidamide; VISUALIZATION; DESIGN; THIOUREA; 4,5-DIHYDRO-1H-PYRAZOLE DERIVATIVES; INOS; POTENT; ENZYME; BIOLOGICAL EVALUATION; INHIBITORS; UREA
• DOI: 10.1016/j.bioorg.2022.105637
• ISSN: 0045-2068

[Display omitted] •Pyridine and imidamide moieties in the design of NOS inhibitors.•Synthesis of twelve new compounds derived from nictotinaldehyde, and description of an unusual cyclization.•Compounds 9a and 9g have shown good inhibition values on the iNOS isoform.•9a has not presented undesirable effects at the cardiovascular level.•Docking studies on 9a and 9g are able to explain selectivity iNOS/nNOS. The selective inhibition of inducible nitric oxide synthase (iNOS) has become an interesting goal for the treatment of diseases where the immune and inflammatory response of the organism is involved. Septic shock is one prominent example of this type of affections. In this paper, the design and synthesis of twelve substituted pyridinyl- imidamide derivatives is described, together with their biological evaluation as NOS inhibitors. The most potent and selective compound was N-(3-hydroxy-3-(pyridin-3-yl)propyl)acetimidamide 9a (IC50 = 4.6 µM, against iNOS). Pharmacological assays in aortic rat tissue, have confirmed its inhibitory activity on iNOS and the absence of undesired cardicovascular effects. In silico analysis of the most promising compounds (9a, 9b, 9e and 9g) have predicted good drug-likeness properties. Furthermore, they have shown an adequate cell viability. Docking studies carried out on 9a suggest a particular binding mode that involves the essential residue Glu377, and might explain its iNOS selectivity. From a chemical point of view, the article describes an unusual cyclization to obtain pyridinyl-pyrimidine derivatives with high yield.