A QSAR study on a series of simplified digitalis-like compounds acting on Na⁺,K⁺-ATPase

Abstract

Among the cardiotonics (agents against congestive heart failure), the most important group is of the digitalis cardiac glycosides, but since these compounds suffer from a low therapeutic index, attention has been paid to investigating safer cardiotonic agents through the inhibition of Na⁺,K⁺-ATPase, the mechanism by which the digitalis cardiac glycosides elicit their action. Recently, a series of perhydroindenes were studied for their Na⁺,K⁺-ATPase inhibition activity. We report here a QSAR study on them to investigate the physicochemical and structural properties of the molecules that govern their activity in order to rationalize the structural modification to have more potent drugs. A multiple regression analysis reveals a significant correlation between the Na⁺,K⁺-ATPase inhibition activity of the compounds and Kier’s first order valence molecular connectivity index of their R₅-substituents and some indicator parameters, suggesting that the R₅-substituents of the compounds containing atoms with low valence and high saturation and the R₁-substituents having =N−O− moiety will be conducive to the activity.