Open AccessDesign, Synthesis, and Biological Evaluation of Tetra‐Substituted Thiophenes as Inhibitors of p38α MAPK
Author(s) -
Vinh Natalie B.,
Devine Shane M.,
Munoz Lenka,
Ryan Renae M.,
Wang Bing H.,
Krum Henry,
Chalmers David K.,
Simpson Jamie S.,
Scammells Peter J.
Publication year - 2015
Publication title -
chemistryopen
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.644
H-Index - 29
ISSN - 2191-1363
DOI - 10.1002/open.201402076
Subject(s) - thiophene , chemistry , mapk/erk pathway , docking (animal) , pyridine , protein kinase a , p38 mitogen activated protein kinases , combinatorial chemistry , stereochemistry , kinase , biochemistry , medicinal chemistry , organic chemistry , medicine , nursing
p38α mitogen‐activated protein kinase (MAPK) plays a role in several cellular processes and consequently has been a therapeutic target in inflammatory diseases, cancer, and cardiovascular disease. A number of known p38α MAPK inhibitors contain vicinal 4‐fluorophenyl/4‐pyridyl rings connected to either a 5‐ or 6‐membered heterocycle. In this study, a small library of substituted thiophene‐based compounds bearing the vicinal 4‐fluorophenyl/4‐pyridyl rings was designed using computational docking as a visualisation tool. Compounds were synthesised and evaluated in a fluorescence polarisation binding assay. The synthesised analogues had a higher binding affinity to the active phosphorylated form of p38α MAPK than the inactive nonphosphorylated form of the protein. 4‐(2‐(4‐fluorophenyl)thiophen‐3‐yl)pyridine had a K i value of 0.6 μ m to active p38α MAPK highlighting that substitution of the core ring to a thiophene retains affinity to the enzyme and can be utilised in p38α MAPK inhibitors. This compound was further elaborated using a substituted phenyl ring in order to probe the second hydrophobic pocket. Many of these analogues exhibited low micromolar affinity to active p38α MAPK. The suppression of neonatal rat fibroblast collagen synthesis was also observed suggesting that further development of these compounds may lead to potential therapeutics having cardioprotective properties.