Synthesis of 4-aryl-3,4-dihydropyrimidin-2(1H)-thione derivatives as potential calcium channel blockers

Biginelli reaction which involves condensation of methyl 3-oxopentanoate, aromatic aldehydes and thiourea with a catalytic amount of HCl at reflux temperature has been used for the synthesis of 4-aryl-6-ethyl-5-(methoxycarbonyl)-3,4-dihydropyrimidin-2(1H)-thiones (1–16). In addition, Lewis acids such as FeCl3·6H2O and/or H3BO3 were also used as catalysts for one-pot synthesis of the products. Compared to the classical Biginelli reaction conditions, the usage of Lewis acids has the advantage of good yields and short reaction times. The calcium channel blocker activities of 1–16 were screened by the tests performed on isolated rat ileum and thoracic aorta. Although product 11, 2-nitrophenyl-derivative, has potent antispasmodic activity on BaCl2-stimulated rat ileum, it does not have vasodilator activity on KCl-stimulated rat thoracic aorta. Product 15, 2-ethoxyphenyl-derivative, exhibited significant antispasmodic and vasodilator activities in both screening paradigms.

4-Aryl-3,4-dihydropyrimidin-2(1H)-thiones were synthesized by Lewis acid-catalyzed Biginelli condensation (Methods B and C). Dihydropyrimidin-2-thiones were obtained in significantly better reaction yields and shorter reaction times than those utilizing the conventional HCl/ethanol method (Method A). The calcium channel blocker activity of the compounds was evaluated.Figure optionsDownload as PowerPoint slide