Design, synthesis and pharmacological evaluation of ester-based quercetin derivatives as selective vascular KCa1.1 channel stimulators

Abstract

Quercetin represents one of the most studied dietary flavonoids; it exerts a panel of pharmacological activities particularly on the cardiovascular system. Stimulation of vascular K_Ca1.1 channels contributes to its vasorelaxant activity, which is, however, counteracted in part by its concomitant stimulation of Ca_V1.2 channels. Therefore, several quercetin hybrid derivatives were designed and synthesized to produce a more selective K_Ca1.1 channel stimulator, then assessed both in silico and in vitro. All the derivatives interacted with the K_Ca1.1 channel with similar binding energy values. Among the selected derivatives, 1E was a weak vasodilator, though displaying an interesting Ca_V1.2 channel blocking activity. The lipoyl derivatives 1F and 3F, though showing pharmacological and electrophysiological features similar to those of quercetin, seemed to be more effective as K_Ca1.1 channel stimulators as compared to the parent compound. The strategy pursued demonstrated how different chemical substituents on the quercetin core can change/invert its effect on Ca_V1.2 channels or enhance its K_Ca1.1 channel stimulatory activity, thus opening new avenues for the synthesis of efficacious vasorelaxant quercetin hybrids.

Keywords: Ca(V)1.2 channel; Ester-based derivatives; Hypertension; K(Ca)1.1 channel; Lipoic acid; Molecular docking; Quercetin; Vasoactivity.