Design, synthesis and pharmacological evaluation of ester-based quercetin derivatives as selective vascular K Ca 1.1 channel stimulators.

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 _Ca 1.1 channels contributes to its vasorelaxant activity, which is, however, counteracted in part by its concomitant stimulation of Ca _V 1.2 channels. Therefore, several quercetin hybrid derivatives were designed and synthesized to produce a more selective K _Ca 1.1 channel stimulator, then assessed both in silico and in vitro. All the derivatives interacted with the K _Ca 1.1 channel with similar binding energy values. Among the selected derivatives, 1E was a weak vasodilator, though displaying an interesting Ca _V 1.2 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 _Ca 1.1 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 _V 1.2 channels or enhance its K _Ca 1.1 channel stimulatory activity, thus opening new avenues for the synthesis of efficacious vasorelaxant quercetin hybrids.
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