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Journal ArticleDOI

Biologically active dihydropyrimidones of the Biginelli-type--a literature survey.

01 Dec 2000-European Journal of Medicinal Chemistry (Eur J Med Chem)-Vol. 35, Iss: 12, pp 1043-1052
TL;DR: This review highlights recent developments in the synthesis of functionalized 3,4-dihydropyrimidin-2(1H)-ones with a focus on the DHPMs recently developed as calcium channel modulators, alpha(1a) adrenoceptor-selective antagonists and compounds that target the mitotic machinery.
About: This article is published in European Journal of Medicinal Chemistry.The article was published on 2000-12-01. It has received 1191 citations till now. The article focuses on the topics: Biginelli reaction & Literature survey.
Citations
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Journal ArticleDOI
TL;DR: Privileged substructures are believed to achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns.
Abstract: Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.

2,620 citations

Journal ArticleDOI
TL;DR: A detailed investigation of several MCRs catalyzed by chiral phosphoric acids that lead to the production of structurally diverse nitrogenous heterocycles is presented, including Biginelli and Biginelli-like reactions; 1,3-dipolar cycloadditions; aza Diels-Alder reactions; and some other cyclization reactions.
Abstract: Optically pure nitrogenous compounds, and especially nitrogen-containing heterocycles, have drawn intense research attention because of their frequent isolation as natural products. These compounds have wide-ranging biological and pharmaceutical activities, offering potential as new drug candidates. Among the various synthetic approaches to nitrogenous heterocycles, the use of asymmetric multicomponent reactions (MCRs) catalyzed by chiral phosphoric acids has recently emerged as a particularly robust tool. This method combines the prominent merits of MCRs with organocatalysis, thus affording enantio-enriched nitrogenous heterocyclic compounds with excellent enantioselectivity, atom economy, bond-forming efficiency, structural diversity, and complexity. In this Account, we discuss a variety of asymmetric MCRs catalyzed by chiral phosphoric acids that lead to the production of structurally diverse nitrogenous heterocycles.In MCRs, three or more reagents are combined simultaneously to produce a single produc...

747 citations

Journal ArticleDOI
TL;DR: There are good reasons why many pharmaceutical companies are incorporating microwave chemistry into their drug discovery efforts and the many advantages of using rapid 'microwave flash heating' for chemical synthesis is the dramatic reduction in reaction times.
Abstract: In the past few years, using microwave energy to heat and drive chemical reactions has become increasingly popular in the medicinal chemistry community. First described 20 years ago, this non-classical heating method has matured from a laboratory curiosity to an established technique that is heavily used in academia and industry. One of the many advantages of using rapid 'microwave flash heating' for chemical synthesis is the dramatic reduction in reaction times--from days and hours to minutes and seconds. As will be discussed here, there are good reasons why many pharmaceutical companies are incorporating microwave chemistry into their drug discovery efforts.

531 citations

Journal ArticleDOI
TL;DR: In this paper, the authors present the methodology and synthetic advantages achieved so far in the asymmetric Mannich reaction, and present a Microreview of the recent contributions to this process.

385 citations

Journal ArticleDOI
TL;DR: An overview of recent literature concerning this topic is presented to provide insight into the applications of multicomponent reactions in this field.
Abstract: Multicomponent reactions are flexible reactions for the rapid generation of complex molecules with often biologically relevant scaffold structures. Combined with the ease of parallelization and the exploratory power with regard to chemical space, multicomponent reactions have attracted significant attention from the medicinal chemistry community. In this Review, we present an overview of recent literature concerning this topic to provide insight into the applications of multicomponent reactions in this field.

361 citations

References
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TL;DR: The prevalence and growth rate of human benign prostatic hyperplasia with age is reported by combining and analyzing data from 10 independent studies containing more than 1,000 prostates.

2,149 citations

Journal ArticleDOI
29 Oct 1999-Science
TL;DR: In vitro, monastrol specifically inhibited the motility of the mitotic kinesin Eg5, a motor protein required for spindle bipolarity, and will therefore be a particularly useful tool for studying mitotic mechanisms.
Abstract: Small molecules that perturb specific protein functions are valuable tools for dissecting complex processes in mammalian cells. A combination of two phenotype-based screens, one based on a specific posttranslational modification, the other visualizing microtubules and chromatin, was used to identify compounds that affect mitosis. One compound, here named monastrol, arrested mammalian cells in mitosis with monopolar spindles. In vitro, monastrol specifically inhibited the motility of the mitotic kinesin Eg5, a motor protein required for spindle bipolarity. All previously known small molecules that specifically affect the mitotic machinery target tubulin. Monastrol will therefore be a particularly useful tool for studying mitotic mechanisms.

1,629 citations

Journal ArticleDOI

1,104 citations

Journal ArticleDOI
Kappe Co1
TL;DR: This Account highlights recent developments in the Biginelli reaction in areas such as solid-phase synthesis, combinatorial chemistry, and natural product synthesis.
Abstract: In 1893, P. Biginelli reported the synthesis of functionalized 3, 4-dihydropyrimidin-2(1H)-ones (DHPMs) via three-component condensation reaction of an aromatic aldehyde, urea, and ethyl acetoacetate. In the past decade, this long-neglected multicomponent reaction has experienced a remarkable revival, mainly due to the interesting pharmacological properties associated with this dihydropyrimidine scaffold. In this Account, we highlight recent developments in the Biginelli reaction in areas such as solid-phase synthesis, combinatorial chemistry, and natural product synthesis.

971 citations

Journal ArticleDOI
TL;DR: The results demonstrate that the active R-(-)-enantiomer 20a of 7 is both more potent and longer acting than nifedipine (1) as an antihypertensive agent in the SHR.
Abstract: In order to explain the potent antihypertensive activity of the modestly active (IC50 = 3.2 microM) dihydropyrimidine calcium channel blocker 5, we carried out drug metabolism studies in the rat and found 5 is metabolized to compounds 6-10. Two of the metabolites, 6 (IC50 = 16 nM) and 7 (IC50 = 12 nM), were found to be responsible for the antihypertensive activity of compound 5. Potential metabolism of 6 into 7 in vivo precluded our interest in pursuing compounds related to 6. Structure-activity studies aimed at identifying additional aryl-substituted analogues of 7 led to 17g,j,p with comparable potential in vivo, though these compounds were less potent than 7 in vitro. To investigate the effects of absolute stereochemistry on potency, we resolved 7 via diastereomeric ureas 19a,b, prepared from 18 by treatment with (R)-alpha-methylbenzylamine. Our results demonstrate that the active R-(-)-enantiomer 20a of 7 is both more potent and longer acting than nifedipine (1) as an antihypertensive agent in the SHR. The in vivo potency and duration of 20a is comparable to the long-acting dihydropyridine amlodipine. The superior oral antihypertensive activity of 20a compared to that of previously described carbamates 2 (R2 = COOEt) could be explained by its improved oral bioavailability, possibly resulting from increased stability of the urea functionality.

745 citations