{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T17:02:21Z","timestamp":1792429341425,"version":"4.5.0"},"reference-count":125,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T00:00:00Z","timestamp":1673481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deputyship for Research &amp; lnnovation","award":["IFP2021-105"],"award-info":[{"award-number":["IFP2021-105"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Hypertension and cardiovascular diseases related to it remain the leading medical challenges globally. Several drugs have been synthesized and commercialized to manage hypertension. Some of these drugs have a dihydropyrimidine skeleton structure, act as efficient calcium channel blockers, and affect the calcium ions\u2019 intake in vascular smooth muscle, hence managing hypertension. The synthesis of such moieties is crucial, and documenting their structure\u2013activity relationship, their evolved and advanced synthetic procedures, and future opportunities in this area is currently a priority. Tremendous efforts have been made after the discovery of the Biginelli condensation reaction in the synthesis of dihydropyrimidines. From the specific selection of Biginelli adducts to the variation in the formed intermediates to achieve target compounds containing heterocylic rings, aldehydes, a variety of ketones, halogens, and many other desired functionalities, extensive studies have been carried out. Several substitutions at the C3, C4, and C5 positions of dihydropyrimidines have been explored, aiming to produce feasible derivatives with acceptable yields as well as antihypertensive activity. The current review aims to cover this requirement in detail.<\/jats:p>","DOI":"10.3390\/molecules28020784","type":"journal-article","created":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T02:57:33Z","timestamp":1673578653000},"page":"784","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Synthesis of Dihydropyrimidines: Isosteres of Nifedipine and Evaluation of Their Calcium Channel Blocking Efficiency"],"prefix":"10.3390","volume":"28","author":[{"given":"Yasser M.","family":"Zohny","sequence":"first","affiliation":[{"name":"Pharmaceutical Sciences Department, College of Pharmacy, Shaqra University, Dawadmi P.O. Box 11961, Saudi Arabia"},{"name":"Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Cairo 11795, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir M.","family":"Awad","sequence":"additional","affiliation":[{"name":"Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein-Helwan, Cairo 11795, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha A.","family":"Rabie","sequence":"additional","affiliation":[{"name":"Pharmacy Practice Department, College of Pharmacy, Shaqra University, Dawadmi P.O. Box 11961, Saudi Arabia"},{"name":"Pharmacology and Toxicology Department, School of Pharmacy, Cairo University, Cairo 11795, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar A.","family":"Al-Saidan","sequence":"additional","affiliation":[{"name":"Pharmaceutics Department, College of Pharmacy, Al-Jouf University, Sakaka P.O. Box 74666, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Tadic, M., Saeed, S., Grassi, G., Taddei, S., Mancia, G., and Cuspidi, C. (2021). Hypertension and COVID-19: Ongoing controversies. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.639222"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.phrs.2017.11.003","article-title":"Hypertension and cardiovascular risk: General aspects","volume":"129","author":"Kjeldsen","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.ejmech.2017.03.025","article-title":"Recent synthetic and medicinal perspectives of dihydropyrimidinones: A review","volume":"132","author":"Kaur","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Marinescu, M. (2021). Biginelli Reaction Mediated Synthesis of Antimicrobial Pyrimidine Derivatives and Their Therapeutic Properties. Molecules, 26.","DOI":"10.3390\/molecules26196022"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1081\/CLT-120023761","article-title":"Glucagon in \u03b2-blocker and calcium channel blocker overdoses: A systematic review","volume":"41","author":"Bailey","year":"2003","journal-title":"J. Toxicol. Clin. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.amjmed.2003.08.027","article-title":"Calcium channel blockers: An update","volume":"116","author":"Eisenberg","year":"2004","journal-title":"Am. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1055\/s-0030-1262512","article-title":"Calcium channel blockers for the management of preterm birth: A review","volume":"28","author":"Nassar","year":"2011","journal-title":"Am. J. Perinatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/s41440-021-00786-z","article-title":"Clinical outcomes of hypertensive patients with COVID-19 receiving calcium channel blockers: A systematic review and meta-analsysis","volume":"45","author":"Kow","year":"2022","journal-title":"Hypertens. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1097\/FJC.0000000000001144","article-title":"Use of Calcium Channel Blockers and the Risk of All-cause Mortality and Severe Illness in Patients With COVID-19: A Systematic Review and Meta-analysis","volume":"79","author":"Kow","year":"2022","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1016\/j.jamda.2020.12.019","article-title":"Antihypertensive medication classes and the risk of dementia: A systematic review and network meta-analysis","volume":"22","author":"Abdulrahman","year":"2021","journal-title":"J. Am. Med. Dir. Assoc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"357","DOI":"10.2165\/00148581-200608060-00004","article-title":"A review of calcium channel antagonists in the treatment of pediatric hypertension","volume":"8","author":"Sahney","year":"2006","journal-title":"Pediatr. Drugs"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Lin, Y.-C., Lin, J.-W., Wu, M.-S., Chen, K.-C., Peng, C.-C., and Kang, Y.-N. (2017). Effects of calcium channel blockers comparing to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with hypertension and chronic kidney disease stage 3 to 5 and dialysis: A systematic review and meta-analysis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0188975"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1021\/cr200251d","article-title":"Synthesis of pyridine and dihydropyridine derivatives by regio-and stereoselective addition to N-activated pyridines","volume":"112","author":"Bull","year":"2012","journal-title":"Chem. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.dit.2013.05.010","article-title":"A review on recent progress in multicomponent reactions of pyrimidine synthesis","volume":"5","author":"Gore","year":"2013","journal-title":"Drug Inven. Today"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ling, Y., Hao, Z.-Y., Liang, D., Zhang, C.-L., Liu, Y.-F., and Wang, Y. (2021). The expanding role of pyridine and dihydropyridine scaffolds in drug design. Drug Des. Devel. Ther., 15.","DOI":"10.2147\/DDDT.S329547"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Borah, B., Patat, M., Swain, S., and Chowhan, L.R. (2022). Recent Advances and Prospects in the Transition-Metal-Free Synthesis of 1,4-Dihydropyridines. ChemistrySelect, 7.","DOI":"10.1002\/slct.202202484"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"133","DOI":"10.2174\/1874467208666150518114857","article-title":"Calcium channel mutations in cardiac arrhythmia syndromes","volume":"8","author":"Betzenhauser","year":"2015","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lam, A., Karekar, P., Shah, K., Hariharan, G., Fleyshman, M., Kaur, H., Singh, H., and Gururaja Rao, S. (2018). Drosophila Voltage-Gated Calcium Channel \u03b11-Subunits Regulate Cardiac Function in the Aging Heart. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-25195-0"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/S0008-6363(99)00038-3","article-title":"Ca channels in cardiac myocytes: Structure and function in Ca influx and intracellular Ca release","volume":"42","author":"Bers","year":"1999","journal-title":"Cardiovasc. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Pach\u00f2n Angona, I., Daniel, S., Martin, H., Bonet, A., Wnorowski, A., Maj, M., J\u00f3\u017awiak, K., Silva, T.B., Refouvelet, B., and Borges, F. (2020). Design, Synthesis and Biological Evaluation of New Antioxidant and Neuroprotective Multitarget Directed Ligands Able to Block Calcium Channels. Molecules, 25.","DOI":"10.3390\/molecules25061329"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kowalska, M., Fija\u0142kowski, \u0141., Kubacka, M., Sa\u0142at, K., Grze\u015bk, G., Nowaczyk, J., and Nowaczyk, A. (2021). Antiepileptic Drug Tiagabine Does Not Directly Target Key Cardiac Ion Channels Kv11.1, Nav1.5 and Cav1.2. Molecules, 26.","DOI":"10.3390\/molecules26123522"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1152\/physrev.1977.57.1.71","article-title":"Calcium release from the sarcoplasmic reticulum","volume":"57","author":"Endo","year":"1977","journal-title":"Physiol. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kushner, J., Ferrer, X., and Marx, S.O. (2019). Roles and Regulation of Voltage-gated Calcium Channels in Arrhythmias. J. Innov. Card. Rhythm Manag., 10.","DOI":"10.19102\/icrm.2019.101006"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/eurheartj\/18.suppl_A.15","article-title":"Molecular basis of the diversity of calcium channels in cardiovascular tissues","volume":"18","author":"Nargeot","year":"1997","journal-title":"Eur. Heart J."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Andrade, F., Rangel-Sandoval, C., Rodr\u00edguez-Hern\u00e1ndez, A., L\u00f3pez-Dyck, E., Elizalde, A., Virgen-Ortiz, A., Bonales-Alatorre, E., Valencia-Cruz, G., and S\u00e1nchez-Pastor, E. (2020). Capsaicin Causes Vasorelaxation of Rat Aorta through Blocking of L-type Ca2+ Channels and Activation of CB1 Receptors. Molecules, 25.","DOI":"10.3390\/molecules25173957"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wu, J., Yan, Z., Li, Z., Yan, C., Lu, S., Dong, M., and Yan, N. (2015). Structure of the voltage-gated calcium channel Cav1. 1 complex. Science, 350.","DOI":"10.1126\/science.aad2395"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.yjmcc.2009.08.021","article-title":"Cardiac T-type Ca2+ channels in the heart","volume":"48","author":"Ono","year":"2010","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.biocel.2019.01.008","article-title":"T-type calcium channels: From molecule to therapeutic opportunities","volume":"108","author":"Weiss","year":"2019","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"61","DOI":"10.2174\/1874467208666150507094022","article-title":"Novel approaches to examine the regulation of voltage-gated calcium channels in the heart","volume":"8","author":"Morrow","year":"2015","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"R227","DOI":"10.1152\/ajpregu.00276.2014","article-title":"Functional importance of T-type voltage-gated calcium channels in the cardiovascular and renal system: News from the world of knockout mice","volume":"308","author":"Hansen","year":"2015","journal-title":"Am. J. Physiol.-Regul. Integr. Comp. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1161\/01.ATV.0000097770.66965.2A","article-title":"Novel vascular biology of third-generation L-type calcium channel antagonists: Ancillary actions of amlodipine","volume":"23","author":"Mason","year":"2003","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1146\/annurev.pa.27.040187.002023","article-title":"Calcium channel ligands","volume":"27","author":"Triggle","year":"1987","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1021\/jm00001a017","article-title":"Calcium entry blockers and activators: Conformational and structural determinants of dihydropyrimidine calcium channel modulators","volume":"38","author":"Rovnyak","year":"1995","journal-title":"J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/0014-2999(86)90417-6","article-title":"The enantiomers of the dihydropyridine derivative H 160\/51 show opposite effects of stimulation and inhibition","volume":"122","author":"Isaksson","year":"1986","journal-title":"Eur. J. Pharmacol."},{"key":"ref_35","first-page":"S350","article-title":"The place of the calcium antagonist verapamil in antihypertensive therapy","volume":"4","author":"Kiowski","year":"1982","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/304635a0","article-title":"Rapid photochemical inactivation of Ca2+-antagonists shows that Ca2+ entry directly activates contraction in frog heart","volume":"304","author":"Morad","year":"1983","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1248\/cpb.37.2117","article-title":"Synthesis of novel 2-chloro-1, 4-dihydropyridines by chlorination of 2-hydroxy-1, 4-dihydropyridines with phosphorus oxychloride","volume":"37","author":"Cho","year":"1989","journal-title":"Chem. Pharm. Bull."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Singh, K., Arora, D., Singh, K., and Singh, S. (2009). Genesis of dihydropyrimidinonep calcium channel blockers: Recent progress in structure-activity relationships and other effects. Mini Rev. Med. Chem., 9.","DOI":"10.2174\/138955709787001686"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1113\/jphysiol.1984.sp015271","article-title":"Extracellular ions and excitation-contraction coupling in frog twitch muscle fibres","volume":"351","author":"Miledi","year":"1984","journal-title":"J. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1139\/y87-112","article-title":"Simultaneous measurements of Ca2+ currents and intracellular Ca2+ concentrations in single skeletal muscle fibers of the frog","volume":"65","author":"Brum","year":"1987","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2270","DOI":"10.1073\/pnas.91.6.2270","article-title":"Biochemical evidence for a complex involving dihydropyridine receptor and ryanodine receptor in triad junctions of skeletal muscle","volume":"91","author":"Marty","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/336134a0","article-title":"Restoration of excitation\u2014Contraction coupling and slow calcium current in dysgenic muscle by dihydropyridine receptor complementary DNA","volume":"336","author":"Tanabe","year":"1988","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1038\/346567a0","article-title":"Regions of the skeletal muscle dihydropyridine receptor critical for excitation\u2013contraction coupling","volume":"346","author":"Tanabe","year":"1990","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"C1","DOI":"10.1152\/ajpcell.1983.245.1.C1","article-title":"Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum","volume":"245","author":"Fabiato","year":"1983","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5725","DOI":"10.1073\/pnas.91.12.5725","article-title":"Membrane repolarization stops caffeine-induced Ca2+ release in skeletal muscle cells","volume":"91","author":"Suda","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1139\/y97-137","article-title":"The voltage-sensitive release mechanism: A new trigger for cardiac contraction","volume":"75","author":"Howlett","year":"1997","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/382719a0","article-title":"Functional coupling between ryanodine receptors and L-type calcium channels in neurons","volume":"382","author":"Chavis","year":"1996","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.3987\/R-1987-05-1189","article-title":"Synthesis of substituted 1, 2, 3, 4-tetrahydro-6-methyl-2-thioxo-5-pyrimidinecarboxylic acid esters","volume":"26","author":"Atwal","year":"1987","journal-title":"Heterocycles"},{"key":"ref_49","unstructured":"Mishina, T., Tsuda, N., Inui, A., and Miura, Y. (1988). Jpn. Kokai Tokkyo Koho (1987) JP 62169793. Chem. Abstr., 108."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1021\/jm00167a035","article-title":"Dihydropyrimidine calcium channel blockers: 2-heterosubstituted 4-aryl-1, 4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines","volume":"33","author":"Atwal","year":"1990","journal-title":"J. Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3254","DOI":"10.1021\/jm00095a023","article-title":"Dihydropyrimidine calcium channel blockers. 4. Basic 3-substituted-4-aryl-1, 4-dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive agents","volume":"35","author":"Rovnyak","year":"1992","journal-title":"J. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Mahgoub, S., Kotb El-Sayed, M.-I., El-Shehry, M.F., Mohamed Awad, S., Mansour, Y.E., and Fatahala, S.S. (2021). Synthesis of novel calcium channel blockers with ACE2 inhibition and dual antihypertensive\/anti-inflammatory effects: A possible therapeutic tool for COVID-19. Bioorg. Chem., 116.","DOI":"10.1016\/j.bioorg.2021.105272"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Irshad, N., Khan, A.-u., Khan, S.-U.-D., and Iqbal, M.S. (2021). Antihypertensive potential of selected pyrimidine derivatives: Explanation of underlying mechanistic pathways. Biomed. Pharmacother., 139.","DOI":"10.1016\/j.biopha.2021.111567"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5135","DOI":"10.1016\/j.tetlet.2016.09.047","article-title":"Biginelli reaction: An overview","volume":"57","author":"Nagarajaiah","year":"2016","journal-title":"Tetrahedron Lett."},{"key":"ref_55","first-page":"2172","article-title":"Vasodilator profile of a new 1, 4-dihydropyridine derivative, 2, 6-dimethyl-4-(3-nitrophenyl)-1, 4-dihydropyridine-3, 5-dicarboxylic acid 3-[2-(N-benzyl-N-methylamino)]-ethyl ester 5-methyl ester hydrochloride (YC-93)","volume":"26","author":"Takenaka","year":"1976","journal-title":"Arzneimittelforschung"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1021\/jm00159a022","article-title":"Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents","volume":"29","author":"Arrowsmith","year":"1986","journal-title":"J. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0223-5234(98)80015-9","article-title":"Asymmetric N-(3, 3-diphenylpropyl) aminoalkyl esters of 4-aryl-2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylic acids with antihypertensive activity","volume":"33","author":"Leonardi","year":"1998","journal-title":"Eur. J. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3787","DOI":"10.1248\/cpb.33.3787","article-title":"New 1, 4-dihydropyridine derivatives with potent and long-lasting hypotensive effect","volume":"33","author":"Meguro","year":"1985","journal-title":"Chem. Pharm. Bull."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"El-Wakil, M.H., Teleb, M., Abu-Serie, M.M., Huang, S., Zamponi, G.W., and Fahmy, H. (2021). Structural optimization, synthesis and in vitro synergistic anticancer activities of combinations of new N3-substituted dihydropyrimidine calcium channel blockers with cisplatin and etoposide. Bioorg. Chem., 115.","DOI":"10.1016\/j.bioorg.2021.105262"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Teleb, M., Rizk, O.H., Zhang, F.-X., Fronczek, F.R., Zamponi, G.W., and Fahmy, H. (2019). Synthesis of some new C2 substituted dihydropyrimidines and their electrophysiological evaluation as L-\/T-type calcium channel blockers. Bioorg. Chem., 88.","DOI":"10.1016\/j.bioorg.2019.04.009"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/S0968-0896(98)00048-0","article-title":"Combinatorial synthesis and screening of a chemical library of 1, 4-dihydropyridine calcium channel blockers","volume":"6","author":"Gordeev","year":"1998","journal-title":"Bioorg. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1002\/anie.199115591","article-title":"1, 4-dihydropyridines: Effects of chirality and conformation on the calcium antagonist and calcium agonist activities","volume":"30","author":"Goldmann","year":"1991","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4901","DOI":"10.2174\/092986711797535173","article-title":"Broccatelli. F.; Zhorov, B.S.; Chiarini, A.; Budriesi, R. 1, 4-Dihydropyridine scaffold in medicinal chemistry, the story so far and perspectives (part 1): Action in ion channels and GPCRs","volume":"18","author":"Ioan","year":"2011","journal-title":"Curr. Med. Chem"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.bioorg.2018.10.054","article-title":"Design, synthesis and pharmacological evaluation of some substituted dihydropyrimidines with L-\/T-type calcium channel blocking activities","volume":"83","author":"Teleb","year":"2019","journal-title":"Bioorg. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1016\/j.bmc.2017.02.015","article-title":"Synthesis and biological evaluation of novel N3-substituted dihydropyrimidine derivatives as T-type calcium channel blockers and their efficacy as analgesics in mouse models of inflammatory pain","volume":"25","author":"Teleb","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Farghaly, A.M., Rizk, O.H., Darwish, I., Hamza, M., Altowyan, M.S., Barakat, A., and Teleb, M. (2022). Design, Synthesis, Pharmacodynamic and In Silico Pharmacokinetic Evaluation of Some Novel Biginelli-Derived Pyrimidines and Fused Pyrimidines as Calcium Channel Blockers. Molecules, 27.","DOI":"10.3390\/molecules27072240"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.ejmech.2017.03.080","article-title":"Synthesis of new N3-substituted dihydropyrimidine derivatives as L-\/T-type calcium channel blockers","volume":"134","author":"Teleb","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Kappe, C.O., Stadler, A., and Dallinger, D. (2012). Microwaves in Organic and Medicinal Chemistry, John Wiley & Sons.","DOI":"10.1002\/9783527647828"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s11030-009-9138-8","article-title":"Controlled microwave heating in modern organic synthesis: Highlights from the 2004\u20132008 literature","volume":"13","author":"Kappe","year":"2009","journal-title":"Mol. Divers."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1039\/B411438H","article-title":"Microwaves in organic synthesis. Thermal and non-thermal microwave effects","volume":"34","author":"Moreno","year":"2005","journal-title":"Chem. Soc. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"441","DOI":"10.2174\/1386207023330147","article-title":"Enhancement of combinatorial chemistry by microwave-assisted organic synthesis","volume":"5","author":"Lidstrom","year":"2002","journal-title":"Comb. Chem. High Throughput Screen."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1021\/op034181b","article-title":"Development and applications of a practical continuous flow microwave cell","volume":"8","author":"Wilson","year":"2004","journal-title":"Org. Process Res. Dev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/nrd1926","article-title":"The impact of microwave synthesis on drug discovery","volume":"5","author":"Kappe","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/S1359-6446(02)02178-5","article-title":"The impact of microwave-assisted organic chemistry on drug discovery","volume":"7","author":"Wathey","year":"2002","journal-title":"Drug Discov. Today"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1021\/cc010044j","article-title":"Automated library generation using sequential microwave-assisted chemistry. Application toward the Biginelli multicomponent condensation","volume":"3","author":"Stadler","year":"2001","journal-title":"J. Comb. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0076-6879(03)69011-7","article-title":"Building dihydropyrimidine libraries via microwave-assisted Biginelli multicomponent reactions","volume":"369","author":"Kappe","year":"2003","journal-title":"Methods Enzymol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4651","DOI":"10.1016\/j.tet.2005.12.061","article-title":"Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters","volume":"62","author":"Desai","year":"2006","journal-title":"Tetrahedron"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1055\/s-1999-3592","article-title":"Microwave-assisted high-speed parallel synthesis of 4-aryl-3, 4-dihydropyrimidin-2 (1H)-ones using a solventless Biginelli condensation protocol","volume":"1999","author":"Kappe","year":"1999","journal-title":"Synthesis"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1021\/cc0601377","article-title":"Microwave-assisted solution-and solid-phase synthesis of 2-amino-4-arylpyrimidine derivatives","volume":"9","author":"Matloobi","year":"2007","journal-title":"J. Comb. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S0968-0896(96)00248-9","article-title":"Synthesis and biological activity of methane sulfonyl pyrrole-substituted 3.5-dihydroxy-6 heptanoates: A novel series of HMG-CoA reductase inhibitors","volume":"5","author":"Watanabe","year":"1997","journal-title":"Bioorg. Med. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"6937","DOI":"10.1016\/S0040-4020(01)87971-0","article-title":"100 years of the Biginelli dihydropyrimidine synthesis","volume":"49","author":"Kappe","year":"1993","journal-title":"Tetrahedron"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1023\/B:MODI.0000006865.59065.bf","article-title":"Microwave-assisted scavenging of electrophiles utilizing polymer-supported sequestration reagents. Application to the synthesis of N3-acylated dihydropyrimidine libraries","volume":"7","author":"Dallinger","year":"2003","journal-title":"Mol. Divers."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1021\/ol034085v","article-title":"High-Throughput Synthesis of N 3-Acylated Dihydropyrimidines Combining Microwave-Assisted Synthesis and Scavenging Techniques","volume":"5","author":"Dallinger","year":"2003","journal-title":"Org. Lett."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1021\/cc0700041","article-title":"5-Aroyl-3,4-dihydropyrimidin-2-one Library Generation via Automated Sequential and Parallel Microwave-assisted Synthesis Techniques","volume":"9","author":"Pisani","year":"2007","journal-title":"J. Comb. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1055\/s-1998-6083","article-title":"New solvent-free organic synthesis using focused microwaves","volume":"1998","author":"Loupy","year":"1998","journal-title":"Synthesis"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1039\/a700838d","article-title":"Iron (III) catalysis of the Michael reaction of 1, 3-dicarbonyl compounds and enones","volume":"10","author":"Christoffers","year":"1997","journal-title":"Chem. Commun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3335","DOI":"10.1081\/SCC-200030577","article-title":"Microwave-assisted efficient synthesis of dihydropyrimidines in solvent-free condition","volume":"34","author":"Bolourtchian","year":"2004","journal-title":"Synth. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1515\/znb-1999-0618","article-title":"Microwave-assisted oxidation of alcohols using wet alumina supported ammonium chlorochromate in solventless system","volume":"54","author":"Heravi","year":"1999","journal-title":"Zeitschrift f\u00fcr Naturforschung B"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1080\/00397910008087395","article-title":"3, 4-Dihydropyrimidin-2 (1H)-ones: Fast synthesis under microwave irradiation in solvent free conditions","volume":"30","author":"Stefani","year":"2000","journal-title":"Synth. Commun."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3454","DOI":"10.1021\/jo970846u","article-title":"Unprecedented catalytic three component one-pot condensation reaction: An efficient synthesis of 5-alkoxycarbonyl-4-aryl-3, 4-dihydropyrimidin-2 (1H)-ones","volume":"63","author":"Hu","year":"1998","journal-title":"J. Org. Chem."},{"key":"ref_91","first-page":"0235","article-title":"A novel Cu-catalysed three-component one-pot synthesis of dihydropyrimidin-2 (1H)-ones using microwaves under solvent-free conditions","volume":"2004","author":"Gohain","year":"2004","journal-title":"Synlett"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1002\/cjoc.20020200417","article-title":"Synthesis of 4-aryl-3, 4-dihydropyrimidinones using microwave-assisted solventless Biginelli reaction","volume":"20","author":"Xue","year":"2002","journal-title":"Chin. J. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"354","DOI":"10.3184\/030823400103167633","article-title":"Microwave-assisted efficient synthesis of dihydro pyrimidines: Improved high yielding protocol for the Biginelli reaction","volume":"2000","author":"Yadav","year":"2000","journal-title":"J. Chem. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2703","DOI":"10.1007\/s11030-021-10360-x","article-title":"Heterogeneous catalyst SiO2\u2013LaCl3 7H2O: Characterization and microwave-assisted green synthesis of \u03b1-aminophosphonates and their antimicrobial activity","volume":"26","author":"Basha","year":"2022","journal-title":"Mol. Divers."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1081\/SCC-120027250","article-title":"A facile and efficient one-pot synthesis of dihydropyrimidinones catalyzed by magnesium bromide under solvent-free conditions","volume":"34","author":"Salehi","year":"2004","journal-title":"Synth. Commun."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1080\/00397911.2011.593289","article-title":"Microwave-assisted and iodine-catalyzed synthesis of dihydropyrimidin-2-thiones via biginelli reaction under solvent-free conditions","volume":"43","author":"Liu","year":"2013","journal-title":"Synth. Commun."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1081\/SCC-200050956","article-title":"Magnesium Chloride Hexahydrate Catalyzed One-Pot Synthesis of 3, 4-Dihydropyrimidin-2-(1 H) ones Under Solvent-Free Conditions","volume":"35","author":"Zhang","year":"2005","journal-title":"Synth. Commun."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"122","DOI":"10.5155\/eurjchem.5.1.122-126.911","article-title":"A microwave-assisted synthesis of 3, 4-dihydropyrimidin-2 (1H)-one\/thione derivatives using nanocrystalline MgFe2O4 as catalyst","volume":"5","author":"Ladole","year":"2014","journal-title":"Eur. J. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0166-1280(93)87073-M","article-title":"Theoretical studies applicable to the design of novel anticonvulsants: Part 2. A comparison of AM1, MNDO, and PM3 semiempirical molecular orbital conformational analyses of dihydropyridine calcium channel blockers","volume":"281","author":"Bikker","year":"1993","journal-title":"J. Mol. Struct. THEOCHEM"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1023\/A:1008272311650","article-title":"Spatial structure of dihydropyridines and similarity of dihydropyridines with some amino acids","volume":"7","author":"Liepina","year":"1997","journal-title":"Mol. Eng."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1039\/c39860000739","article-title":"A conformational distinction between dihydropyridine calcium agonists and antagonists","volume":"10","author":"Mahmoudian","year":"1986","journal-title":"J. Chem. Soc. Chem. Commun."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.1007\/s00044-011-9807-x","article-title":"Synthesis, calcium-channel blocking activity, and conformational analysis of some novel 1, 4-dihydropyridines: Application of PM3 and DFT computational methods","volume":"21","author":"Fassihi","year":"2012","journal-title":"Med. Chem. Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1007\/s00044-009-9171-2","article-title":"Computational studies of new 1, 4-dihydropyridines containing 4-(5)-chloro-2-ethyl-5-(4)-imidazolyl substituent: QSAR and docking","volume":"19","author":"Davood","year":"2010","journal-title":"Med. Chem. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2803","DOI":"10.1016\/S0040-4020(97)00022-7","article-title":"Conformational analysis of 4-aryl-dihydropyrimidine calcium channel modulators. A comparison of ab initio, semiempirical and X-ray crystallographic studies","volume":"53","author":"Kappe","year":"1997","journal-title":"Tetrahedron"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"99","DOI":"10.5012\/jkcs.2013.57.1.99","article-title":"Pharmacophore modelling, quantitative structure activity relationship (QSAR) and docking studies of pyrimidine analogs as potential calcium channel blockers","volume":"57","author":"Choudhari","year":"2013","journal-title":"J. Korean Chem. Soc."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.theochem.2004.10.071","article-title":"Conformational analysis of some new derivatives of 4-nitroimidazolyl-1,4-dihydropyridine-based calcium channel blockers","volume":"717","author":"Hemmateenejad","year":"2005","journal-title":"J. Mol. Struct. THEOCHEM"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1016\/j.bmc.2004.01.034","article-title":"First pharmacophoric hypothesis for T-type calcium channel blockers","volume":"12","author":"Doddareddy","year":"2004","journal-title":"Bioorg. Med. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.jare.2016.09.004","article-title":"In silico identification of T-type calcium channel blockers: A ligand-based pharmacophore mapping approach","volume":"7","author":"Gandhi","year":"2016","journal-title":"J. Adv. Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1023\/A:1023632419813","article-title":"1, 4-Dihydropyridines as calcium channel ligands and privileged structures","volume":"23","author":"Triggle","year":"2003","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/med.10060","article-title":"KATP channel openers: Structure-activity relationships and therapeutic potential","volume":"24","author":"Mannhold","year":"2004","journal-title":"Med. Res. Rev."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/(SICI)1098-2299(199909)48:1<26::AID-DDR4>3.0.CO;2-M","article-title":"Synthesis of valproate, valerate, and 1-methyl-1, 4-dihydropyridyl-3-carbonyloxy ester derivatives of Hantzsch 1, 4-dihydropyridines as potential prodrugs and their evaluation as calcium channel antagonist and anticonvulsant agents","volume":"48","author":"Yiu","year":"1999","journal-title":"Drug Dev. Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/S0091-3057(01)00468-3","article-title":"Amlodipine enhances the activity of antiepileptic drugs against pentylenetetrazole-induced seizures","volume":"68","author":"Mazurek","year":"2001","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_113","first-page":"25","article-title":"Improved delivery through biological membranes. XXX. Synthesis and biological aspects of a 1, 4-dihydropyridine based chemical delivery system for brain-sustained delivery of hydroxy CCNU","volume":"2","author":"Raghavan","year":"1987","journal-title":"Anticancer Drug Des."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1002\/ardp.200300760","article-title":"Synthesis, in vitro and in vivo evaluation of a delivery system for targeting anticancer drugs to the brain","volume":"336","author":"Sultan","year":"2003","journal-title":"Arch. Der Pharm. Int. J. Pharm. Med. Chem."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1016\/S0968-0896(01)00141-9","article-title":"Synthesis and QSAR studies of 4-substituted phenyl-2, 6-dimethyl-3, 5-bis-N-(substituted phenyl) carbamoyl-1, 4-dihydropyridines as potential antitubercular agents","volume":"9","author":"Desai","year":"2001","journal-title":"Bioorg. Med. Chem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1016\/j.bmc.2008.12.070","article-title":"Synthesis and biological evaluation of some new 1, 4-dihydropyridines containing different ester substitute and diethyl carbamoyl group as anti-tubercular agents","volume":"17","author":"Khoshneviszadeh","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_117","first-page":"219","article-title":"Effect of new and known 1, 4-dihydropyridine derivatives on blood glucose levels in normal and streptozotocin-induced diabetic rats","volume":"22","author":"Briede","year":"2004","journal-title":"Cell Biochem. Funct. Cell. Biochem. Its Modul. Act. Agents Dis."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.neuroscience.2003.12.005","article-title":"Inhibition of type A GABA receptors by L-type calcium channel blockers","volume":"124","author":"Das","year":"2004","journal-title":"Neuroscience"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1007\/s10517-017-3610-8","article-title":"Evaluation of the hepatoprotective effect of L-ascorbate 1-(2-hydroxyethyl)-4, 6-dimethyl-1, 2-dihydropyrimidine-2-one upon exposure to carbon tetrachloride","volume":"162","author":"Vyshtakalyuk","year":"2017","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1016\/j.bbagen.2018.07.022","article-title":"Structural basis for the hepatoprotective effects of antihypertensive 1, 4-dihydropyridine drugs","volume":"1862","author":"Wei","year":"2018","journal-title":"Biochim. Biophys. Acta (BBA)-Gen. Subj."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Rami, C., Patel, L., Patel, C.N., and Parmar, J.P. (2013). Synthesis, antifungal activity, and QSAR studies of 1, 6-dihydropyrimidine derivatives. J. Pharm. Bioallied Sci., 5.","DOI":"10.4103\/0975-7406.120078"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.saa.2012.12.069","article-title":"Synthesis, antibacterial and antifungal evaluation of novel 1, 4-dihydropyridine derivatives","volume":"113","year":"2013","journal-title":"Spectrochim. Acta Part A Mol. Biomol. Spectrosc."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/1755-5922.12138","article-title":"Calcium-channel blockers attenuate the antiplatelet effect of clopidogrel","volume":"33","author":"Gremmel","year":"2015","journal-title":"Cardiovasc. Ther."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Park, S.H., Rha, S.-W., Shin, W.-Y., Lee, S.-J., Jin, D.-K., Lee, S.-W., Park, J.Y., Choi, B.G., Poddar, K.L., and Kumari, M. (2011). AS-160 Calcium channel blockers of dihydropyridine class reduce the antiplatelet effect of Clopidogrel?: What is clinical impact. Am. J. Cardiol., 107.","DOI":"10.1016\/j.amjcard.2011.02.109"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.bmc.2005.09.014","article-title":"Microwave-assisted synthesis of antimicrobial dihydropyridines and tetrahydropyrimidin-2-ones: Novel compounds against aspergillosis","volume":"14","author":"Chhillar","year":"2006","journal-title":"Bioorg. Med. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/2\/784\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:04:35Z","timestamp":1760119475000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/2\/784"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,12]]},"references-count":125,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["molecules28020784"],"URL":"https:\/\/doi.org\/10.3390\/molecules28020784","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,12]]}}}