Biginelli dihydropyrimidines and their acetylated derivatives as L-/T-type calcium channel blockers: Synthesis, enantioseparation, and molecular modeling studies

Abstract

Biginelli dihydropyrimidines (DHPMs) are considered superior over 1,4-dihydropyridines (DHPs) in terms of both light and metabolic stabilities. Nevertheless, DHPs dominate the market as the most prescribed calcium channel blockers with strong therapeutic potential in managing cardiovascular ailments. To overcome the restrictions that complicate the formulation and postadministration of DHPs, employing bioisosteric replacement by exchanging the DHP ring with DHPM appears as a logical approach for the improved formulations of new calcium channel blockers. In this study, we obtained DHPM derivatives via Biginelli synthesis and acetylated their N-3 position by heating them in acetic anhydride (GD1–GD12). We also incorporated the DHPM scaffold into a condensed ring system (GD13 and GD14). These DHPMs were evaluated for their ability to block both L- (Ca_v1.2) and T- (Ca_v3.2) type calcium channels. Compounds carrying acetyl moiety on the N-3 position of the DHPM scaffold appeared to be more effective inhibitors of both channels. Retesting GD4 enantiomers, separated using high-performance liquid chromatography (HPLC) on a chiral stationary phase, revealed that the (R)-isomer predominantly contributes to the outstanding inhibitory activity of GD4 on calcium channels. Molecular modeling studies, including docking, molecular dynamics simulations, and dynophore analysis, provided insights into the binding mechanism of DHPMs to Ca_v1.2 and Ca_v3.2, for the first time.