Quercetin represents one of the most studied dietary flavonoids; it exerts a panel of pharmacological activities particularly on the cardiovascular system. Stimulation of vascular K1.1 channels contributes to its vasorelaxant activity, which is, however, counteracted in part by its concomitant stimulation of Ca1.2 channels. Therefore, several quercetin hybrid derivatives were designed and synthesized to produce a more selective K1.1 channel stimulator, then assessed both in silico and in vitro. All the derivatives interacted with the K1.1 channel with similar binding energy values. Among the selected derivatives, 1E was a weak vasodilator, though displaying an interesting Ca1.2 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 K1.1 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 Ca1.2 channels or enhance its K1.1 channel stimulatory activity, thus opening new avenues for the synthesis of efficacious vasorelaxant quercetin hybrids.Copyright © 2020 Elsevier Inc. All rights reserved.