QSAR study on aminophenylbenzamides and acrylamides as histone deacetylase inhibitors: An insight into the structural basis of antiproliferative activity

Abstract

Histone deacetylases have emerged as important drug target with a multitude of therapeutic potentials for their inhibitors. With the purpose of designing new chemical entities with enhanced inhibitory potencies against histone deacetylases, a two-dimensional (2D) quantitative structure-activity relationship (QSAR) study was carried out on aminophenylbenzamides and acrylamide derivatives as inhibitors of these deacetylases. The developed model was validated by standard QSAR parameters and through a detailed structural analysis of how it reproduces and explains the differences in the experimentally known activity data. The model showed a good correlative and predictive ability, with a cross-validated correlation coefficient of 0.594. The conventional and predictive correlation coefficients were found to be 0.725 and 0.577 for the antiproliferative activity of aminophenylbenzamides and acrylamide series, respectively. The study indicated that their antiproliferative activity is largely explained by the steric factors of the substituents, highlighting the role of the size and shape of the inhibitor in forming effective binding interactions with histone deacetylase. The models could be usefully employed to design inhibitors with greatly enhanced potency and selectivity.