Bioactive imidamide-based compounds targeted against nitric oxide synthase Arias Bordajandi, Fabio Franco Montalbán, Francisco Romero Pérez, Miguel Duarte Pérez, Juan Manuel Carrión Peregrina, María Dora Camacho Quesada, Encarnación Synthesis Nitric Oxide Synthase Inhibitors Inducible Nitric Oxide Synthase Inducible Nitric Oxide Synthase Imidamide Septic shock 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. 2022-02-08T08:35:27Z 2022-02-08T08:35:27Z 2022-02-02 journal article Arias F., Franco-Montalban F., Romero, M., Duarte, J.M., Carrión M.D., Camacho M.E.. Bioactive imidamide-based compounds targeted against nitric oxide synthase. Bioorg. Chem. 120 (2022) 105637. https://doi.org/10.1016/j.bioorg.2022.105637 http://hdl.handle.net/10481/72710 https://doi.org/10.1016/j.bioorg.2022.105637 eng http://creativecommons.org/licenses/by-nc-nd/3.0/ open access Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License Elsevier