Multipotent drugs with cholinergic and neuroprotective properties for the treatment of Alzheimer and neuronal vascular diseases. I. Synthesis, biological assessment, and molecular modeling of simple and readily available 2-aminopyridine-, and 2-chloropyridine-3,5-dicarbonitriles

Bioorganic & Medicinal Chemistry
Abdelouahid SamadiCristóbal de Los Ríos

Abstract

The synthesis, molecular modeling, and pharmacological analysis of new multipotent simple, and readily available 2-aminopyridine-3,5-dicarbonitriles (3-20), and 2-chloropyridine-3,5-dicarbonitriles (21-28), prepared from 2-amino-6-chloropyridine-3,5-dicarbonitrile (1) and 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile (2) is described. The biological evaluation showed that some of these molecules were modest inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), in the micromolar range. The 2-amino (3, 4), and 2-chloro derivatives 21-23, 25, 26 were AChE selective inhibitors, whereas 2-amino derivatives 5, 14 proved to be selective for BuChE. Only inhibitor 24 was equipotent for both cholinesterases. Kinetic studies on compound 23 showed that this compound is a mixed-type inhibitor of AChE showing a K(i) of 6.33 microM. No clear SAR can be obtained form these data, but apparently, compounds bearing small groups such as the N,N'-dimethylamino or the pyrrolidino, regardless of the presence of a 2-amino, or 6-chloro substituent in the pyridine ring, preferentially inhibit AChE. Molecular modeling on inhibitors 4, 5, 22, and 23 has been carried out to give a better insight into the binding mode on the ca...Continue Reading

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Citations

Mar 25, 2011·Chemical Communications : Chem Comm·David SucunzaJosé Marco-Contelles
Jan 5, 2012·International Journal of Alzheimer's Disease·Mona MehtaMarwan Sabbagh
Apr 1, 2015·Future Medicinal Chemistry·M Amélia Santos, Sílvia Chaves
Nov 11, 2020·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Óscar M Bautista-AguileraMarta Pérez
May 28, 2019·International Journal of Biological Macromolecules·Masihuz ZamanRizwan Hasan Khan
Feb 15, 2011·Pharmacology, Biochemistry, and Behavior·Alvin V TerryScott J Webster
May 14, 2011·Current Opinion in Pediatrics

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