Review
Biologically active dihydropyrimidones of the Biginelli-type — a literature survey

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Abstract

In 1893, the synthesis of functionalized 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) via three-component condensation reaction of an aromatic aldehyde, urea and ethyl acetoacetate was reported for the first time by P. Biginelli. In the past decades, such Biginelli-type dihydropyrimidones have received a considerable amount of attention due to the interesting pharmacological properties associated with this heterocyclic scaffold. In this review, we highlight recent developments in this area, with a focus on the DHPMs recently developed as calcium channel modulators, α1a adrenoceptor-selective antagonists and compounds that target the mitotic machinery.

Introduction

Over 100 years ago, 4-aryl-3,4-dihydropyrimidin-2(1H)-ones of type 1 (DHPMs) were reported for the first time in the literature. In 1893, the Italian chemist Pietro Biginelli discovered a multicomponent reaction that produced these multifunctionalized dihydropyrimidones 1, in a simple one-pot process (see figure 1) [1]. This efficient approach to partly reduced pyrimidines was largely ignored in the following decades and therefore, the pharmacological properties of this interesting heterocyclic scaffold remained unexplored. Since the early 1980s, however, interest in dihydropyrimidones of type 1 has increased significantly [2]. This was originally due to the apparent structural similarity of DHPMs to the well-known dihydropyridine calcium channel modulators of the Hantzsch type (e.g. 2, DHPs, see figure 2) [3]. It was soon established that DHPMs exhibit a similar pharmacological profile to DHP calcium channel modulators of the nifedipine type and much activity has been observed in this area throughout the 1980s and 1990s [2], [3], [4], [5]. More recently, interest has shifted from DHPM calcium channel modulators to other biologically active DHPM derivatives, e.g. α1a adrenoceptor-selective antagonists, useful for the treatment of benign prostatic hyperplasia [6]. Again, the pharmacological activity in the area of α1 adrenergic antagonists is based on activity found earlier in the DHP series of compounds. However, dihydropyrimidones of type 1 represent much more than just being aza-analogs of dihydropyridines of the Hantzsch type. The advent of combinatorial chemistry, which has proven particularly useful for multicomponent reactions such as the Biginelli condensation [7], allows the efficient generation of diverse DHPM compound libraries that have been subjected to high throughput screening (HTS) processes. Interesting biological effects have been discovered using HTS techniques. The recent identification of a DHPM analog as a potential new anticancer lead that is involved in blocking mitosis by inhibition of a kinesin motor protein is just one example [8].

In this review, we provide a literature overview on the biologically active DHPM analogs. The focus of this article will be on recent pharmacological results in the area of DHPM calcium channel modulators and α1a adrenoceptor-selective antagonists. Although several natural marine products, with interesting biological activities — such as the anti-HIV alkaloid batzelladine B [9] — containing the DHPM core, have recently been reported in the literature, these are not covered in the present article since much of the information on these cyclic guanidinium alkaloids has been presented in a recent review [10]. Since the synthesis of DHPMs 1 is relatively straightforward and has been the focus of other recent review articles [2], [7], only a brief account on synthetic methods will be given here. Patents are only cited if they contain valuable pharmacological information which otherwise has not been published.

Section snippets

Synthesis

Two different approaches have been employed in recent years to synthesize DHPM derivatives. The first method relies on the traditional Biginelli three-component protocol and involves the acid-catalyzed cyclocondensation of a 1,3-dicarbonyl component (3), with an aromatic aldehyde (4) and urea or thiourea derivative (5) (figure 1) [1], [2]. A major drawback of the original Biginelli protocols, using ethanol and catalytic HCl as reaction medium, has been the low yields that were frequently

Geometry and conformation

A prerequisite for any understanding of the interaction of DHPMs with known biological targets at the molecular level is the knowledge of the molecular geometry and accessible conformations of the DHPMs in question. The conformational features of DHPMs have therefore been studied extensively by computational (semiempirical and ab initio), X-ray diffraction and NMR studies [14], [15], [16], [17], [18], [19]. In general, DHPMs of type 1 are conformationally rather flexible molecules, in which the

Calcium channel modulators

4-Aryl-1,4-dihydropyridines (DHPs, e.g. nifedipine, 12) are the most studied class of organic calcium channel modulators and, since their introduction into clinical medicine in 1975, have become almost indispensable for the treatment of cardiovascular diseases, such as hypertension, cardiac arrhythmias or angina [21]. More than 25 years after the introduction of nifedipine (12), many DHP analogs have now been synthesized and numerous second-generation commercial products have appeared on the

α1a-Adrenergic receptor antagonists

Benign prostatic hyperplasia (BPH) is a progressive enlargement of the prostate, resulting in a number of obstructive and irritative symptoms [56]. The incidence of BPH increases with advancing age, such that ca. 70% of males, >70 years-old, manifest symptoms associated with BPH [57]. Nonselective α1-adrenoceptor antagonists, e.g. terazosin, are currently being approved pharmaceuticals commonly employed for the treatments of BPH [58]. It has been reported, however, that the functional potency

Mitotic Kinesin inhibitors

A common strategy for cancer therapy is the development of drugs that interrupt the cell cycle during the mitosis stage. Compounds that perturb microtubule shortening (depolymerization) or lengthening (polymerization) cause arrest of the cell cycle in mitosis due to perturbation of the normal microtubule dynamics necessary for chromosome movement. A variety of such drugs that bind to tubulin and thus inhibit spindle assembly are currently used in cancer therapy (e.g. paclitaxel, docetaxel) [66].

Miscellaneous biological effects

As early as the 1940's DHPMs of type 1 were shown to possess antiviral activity [68]. Eventually, the nitrofuryl-substituted analog nitractin (46) (figure 13) was developed, which displayed good activity against the viruses of the trachoma group [69], [70], [71], in addition to showing modest antibacterial activity [72]. Other structurally simple DHPMs were screened as antitumor agents and found to be active against, for example, Walker carcinosarcoma in rats and mice [73], [74], [75].

Conclusions

Dihydropyrimidines (DHPMs) of the Biginelli-type have come a long way since their discovery in 1893 and the first patent on DHPM derivatives in 1930, describing agents for the protection of wool against moths [87]. During the last 20 years extensive studies on the pharmacology of this ring system have been reported, with an initial focus on developing calcium channel blockers that possess superior pharmacological profiles to Hantzsch-type dihydropyridines. Now, at the beginning of the 21st

Acknowledgments

Our work in the area of dihydropyrimidine chemistry is generously supported by the Austrian Academy of Sciences (APART 319), the Austrian Science Fund (P-11994-CHE) and the ‘Jubiläumsfonds der Österreichischen Nationalbank’ (Project 7904).

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