Quantitative Structure Activity Analysis of 2-Alkoxydihydrocinnamates as PPARα /γ Dual Agonist

P.   Manoj   Kumar; R.      Hemalatha; S.   C.   Mahajan; C.      Karthikeyan; N.   S.   Hari Narayana Moorthy; Piyush      Trivedi

Abstract

To optimize the physiochemical properties of 2-alkoxydihydrocinnamates as PPARα/γ dual agonist, a quantitative structure activity relationship, Hansch approach was made using combination of various thermodynamic, electronic and spatial descriptors. Several regression expressions are obtained using multiple linear regression analysis. The best QSAR model is further validated by leave-one-out cross validation method. Analyses of results from the present QSAR study suggest that for favorable dual PPARα/γ agonist activity electronic property of the substituents in hydrophobic tail phenyl ring plays a key role. The contribution of Hammett constant and dipole moment in the models deduced the importance of electron withdrawing substituents for dual activity. Additionally the study also indicates that bulky substituents in head acid moiety not confer selectivity towards the PPAR activity. Thus the QSAR study brings important structural insight to aid the design of dual PPARα/γ receptor agonist.

Keywords: QSAR, diabetes, hansch analysis, PPARα, PPARγ, hammett constant, dipole moment, heat of formation