Dihydropyrimidine calcium channel blockers: 2-heterosubstituted 4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines

Abstract

2-Heterosubstituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecar box ylic acid esters 8, which lack the potential CS symmetry of dihydropyridine calcium channel blockers, were prepared and evaluated for biological activity. Biological assays using potassium-depolarized rabbit aorta and radioligand binding techniques showed that some of these compounds are potent mimics of dihydropyridine calcium channel blockers. The combination of a branched ester (e.g. isopropyl, sec-butyl) and an alkylthio group (e.g. SMe) was found to be optimal for biological activity. When compared directly with similarly substituted 2-heteroalkyldihydropyridines 9, dihydropyrimidines 8 were found to be 30-fold less active. The solid-state structure of dihydropyrimidine analogue 8g shows that these compounds can adopt a molecular conformation which is similar to the reported conformation of dihydropyridine calcium channel blockers.

Synthesis, characterization and biological evaluation of thiazolopyrimidine derivatives

“…[1][2][3] In recent years, interest has also been focused on aza-analogs of 1,4-dihydropyridines such as dihydropyrimidines (DHPMs), which exhibit a pharmacological profile similar to classical dihydropyridine calcium channel modulators. [4][5][6][7][8][9][10] Apart from being well known for their calcium channel blocking activity, the dihydropyrimidines are also being explored for their possible therapeutic effects in treatment of AIDS. 11 This is due to the fact that their particular structure has been found in the natural marine alkaloids batzelladine A and B, which are the first lowmolecular-weight natural products reported in the literature to inhibit the binding of HIV gp-120 to CD4 cells, thus opening up a new area in the development of AIDS therapy.…”

Synthesis of Some Hexahydroquinazolinones Using K<sub>3</sub>AlF<sub>6</sub>(Al<sub>2</sub>O<sub>3</sub>/KF) as an Efficient Catalyst in Some Hexahydroquinazolinone Derivatives

“…Some of 3,4-DHPMs derivatives are also used as calcium [6]. However, some of the cores of 3,4-DHPMs have an antiviral, antibacterial, antihypertensive and antitumor activities [7] [8]. Also, among them, 3,4-DHPMs derivatives, which are found as core units in many marine alkaloids, have been found to be potent HIV gp-120CD4 inhibitors [9] [10] [11] [12].…”

A One-pot Multi-component Synthesis of Dihydropyrimidinone/Thione and Dihydropyridine Derivatives via Biginelli and Hantzsch Condensations using t-BuOK as a Catalyst Under Solvent-free Conditions

“…Several alkaloids isolated from marine sources also exhibit interesting biological activities, molecular structures of which contain the dihydropyrimidinone moiety [20]. Therefore, their synthesis has been the focus of great interest for organic and medicinal chemists [21]. The original Biginelli protocol for the preparation of DHPMs consisted of heating a mixture of three components which included β-ketoester, aldehyde and urea in ethanol containing a catalytic amount of HCl [22].…”