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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
Author(s) -
Shaik Khasim,
Deb Pran Kishore,
Mailavaram Raghu Prasad,
Chandrasekaran Balakumar,
Kachler Sonja,
Klotz KarlNorbert,
Jaber Abdul Muttaleb Yousef
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13528
Subject(s) - chemistry , selectivity , moiety , pyridine , aryl , stereochemistry , ring (chemistry) , thiophene , adenosine receptor , ligand (biochemistry) , medicinal chemistry , receptor , agonist , organic chemistry , biochemistry , alkyl , catalysis
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 ( AR s). 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 AR s, 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.