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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 <jats:italic>N<\/jats:italic>\u20103 position by heating them in acetic anhydride (<jats:bold>GD1<\/jats:bold>\u2013<jats:bold>GD12<\/jats:bold>). We also incorporated the DHPM scaffold into a condensed ring system (<jats:bold>GD13<\/jats:bold> and <jats:bold>GD14<\/jats:bold>). These DHPMs were evaluated for their ability to block both L\u2010 (Ca<jats:sub>v<\/jats:sub>1.2) and T\u2010 (Ca<jats:sub>v<\/jats:sub>3.2) type calcium channels. Compounds carrying acetyl moiety on the <jats:italic>N<\/jats:italic>\u20103 position of the DHPM scaffold appeared to be more effective inhibitors of both channels. Retesting <jats:bold>GD4<\/jats:bold> enantiomers, separated using high\u2010performance liquid chromatography (HPLC) on a chiral stationary phase, revealed that the (<jats:italic>R<\/jats:italic>)\u2010isomer predominantly contributes to the outstanding inhibitory activity of <jats:bold>GD4<\/jats:bold> on calcium channels. Molecular modeling studies, including docking, molecular dynamics simulations, and dynophore analysis, provided insights into the binding mechanism of DHPMs to Ca<jats:sub>v<\/jats:sub>1.2 and Ca<jats:sub>v<\/jats:sub>3.2, for the first time.<\/jats:p>","DOI":"10.1002\/ardp.202400584","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T13:34:25Z","timestamp":1742996065000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Biginelli dihydropyrimidines and their acetylated derivatives as L\u2010\/T\u2010type calcium channel blockers: Synthesis, enantioseparation, and molecular modeling studies"],"prefix":"10.1002","volume":"358","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2287-9509","authenticated-orcid":false,"given":"Miyase G\u00f6zde","family":"G\u00fcnd\u00fcz","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Hacettepe University, S\u0131hhiye Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cagatay","family":"Dengiz","sequence":"additional","affiliation":[{"name":"Department of Chemistry Middle East Technical University Ankara Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Denzinger","sequence":"additional","affiliation":[{"name":"Molecular Design Group, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy Freie Universit\u00e4t Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute University of Calgary Calgary Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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