Artificial intelligence-driven identification of morin analogues acting as CaV1.2 channel blockers: Synthesis and biological evaluation.

[Display omitted] • Artificial intelligence accelerates the drug discovery. • O -substituted morin derivatives show interesting vasorelaxant activity. • Ca V 1.2 channels seem to be the main targets involved in the vasorelaxant activity. • The pentamethyl derivative 5a reveals a multi-target activity. Morin is a vasorelaxant flavonoid, whose activity is ascribable to Ca V 1.2 channel blockade that, however, is weak as compared to that of clinically used therapeutic agents. A conventional strategy to circumvent this drawback is to synthesize new derivatives differently decorated and, in this context, morin-derivatives able to interact with Ca V 1.2 channels were found by employing the potential of PLATO in target fishing and reverse screening. Three different derivatives (5a - c) were selected as promising tools, synthesized, and investigated in in vitro functional studies using rat aorta rings and rat tail artery myocytes. 5a - c were found more effective vasorelaxant agents than the naturally occurring parent compound and antagonized both electro- and pharmaco-mechanical coupling in an endothelium-independent manner. 5a , the series' most potent, reduced also Ca2+ mobilization from intracellular store sites. Furthermore, 5a ≈ 5c > 5b inhibited Ba2+ current through Ca V 1.2 channels. However, compound 5a caused also a concentration-dependent inhibition of K Ca 1.1 channel currents. [ABSTRACT FROM AUTHOR]