7‐Amino‐2‐aryl/hetero‐aryl‐5‐oxo‐5,8‐dihydro[1,2,4]triazolo[1,5‐a]pyridine‐6‐carbonitriles: Synthesis and adenosine receptor binding studies

Abstract

A series of novel 7-amino-5-oxo-2-substituted-aryl/hetero-aryl-5, 8-dihydro[1,2,4] triazolo[1,5-a]pyridine-6-carbonitriles (4a-4t) was synthesized, characterized and evaluated for their binding affinity and selectivity towards hA 1 , hA 2A , hA 2B and hA 3 adenosine receptors (ARs). Compound 4a with a phenyl ring at 2-position of the triazolo moiety of the scaffold showed high affinity and selectivity for hA 1 AR (K i hA 1 = 0.076 μM, hA 2A = 25.6 μM and hA 3 > 100 μM). Introduction of various electron donating and withdrawing groups at different positions of the phenyl ring resulted in drastic reduction in affinity and selectivity towards all the ARs, except compound 4b with a 4-hydroxyphenyl group at 2-position. Interestingly, the replacement of the phenyl ring with a smaller heterocyclic thiophene ring (π excessive system) resulted in further improvement of affinity for hA 1 AR of compound 4t (K i hA 1 = 0.051 μM, hA 2A = 9.01 μM and hA 3 > 13.9 μM) while retaining the significant selectivity against all other AR subtypes similar to compound 4a. The encouraging results for compounds 4a and 4t indicate that substitution at 2-position of the scaffold with π-excessive systems other than thiophene may lead to even more potent and selective hA 1 AR antagonists. K E Y W O R D SA 1 adenosine receptors, adenosine receptor antagonists, cyanoacetic hydrazides, triazolopyridines

Fused Pyridine Derivatives: Synthesis and Biological Activities

“…Lastly, compounds containing triazolopyridine ring were evaluated for their bioactivities, such as anti-inflammatory, p38R, 11beta-hydroxysteroid dehydrogenase-type 1 (11beta-HSD-1), prolylhydroxylase domain-1 (PHD-1), myeloperoxidase, tubulin polymerization, polycomb repressive complex 2 (PRC2) inhibitory, HIV-1 allosteric inhibitor activity, mGlu receptor 2 (mGluR2) PAM, muscarinic acetylcholine receptor subtype 1 (M1) PAM, and retinoic acid receptor-related orphan nuclear receptor gama-t (RORγt) inverse agonist [174,[291][292][293][294][295][296][297][298][299][300][301][302][303].…”

Exploring Chemistry with Pyridine Derivatives

“…Lastly, compounds containing triazolopyridine ring were evaluated for their bioactivities, such as anti-inflammatory, p38R, 11beta-hydroxysteroid dehydrogenase-type 1 (11beta-HSD-1), prolylhydroxylase domain-1 (PHD-1), myeloperoxidase, tubulin polymerization, polycomb repressive complex 2 (PRC2) inhibitory, HIV-1 allosteric inhibitor activity, mGlu receptor 2 (mGluR2) PAM, muscarinic acetylcholine receptor subtype 1 (M1) PAM, and retinoic acid receptor-related orphan nuclear receptor gama-t (RORγt) inverse agonist [174,[291][292][293][294][295][296][297][298][299][300][301][302][303].…”

Methylene Components Exchange in the Reaction of Cyanoacetohydrazide with 2-Amino-4-arylbuta-1,3-diene-1,1,3-tricarbonitriles

“…Yield 38%, beige powder, mp 185-187°С (mp 186-188°C [52]). IR spectrum, ν, cm -1 : 3200, 3068 s (N-H), 2255 w (C≡N), 1688 s (C=O), 1666 s (C=N, C=C).…”