Our results indicate that individuals infected with CagA+ H. pylori strains and those infected with VacA s1 and m1 strains have an increased risk for gastric cancer. Cohort studies are welcome to integrate this information in the management of at-risk individuals such as those with precancerous cancer conditions and/or a family history of gastric cancer.

Peptidomimetic imidazolidin-4-one derivatives of primaquine (imidazoquines) recently displayed in vitro activity against blood schizonts of a chloroquine-resistant strain of Plasmodium falciparum. Preliminary studies with a subset of such imidazoquines showed them to both block transmission of P. berghei malaria from mouse to mosquito and be highly stable towards hydrolysis at physiological conditions. This prompted us to have deeper insight into the activity of imidazoquines against both Plasmodia and Pneumocystis carinii, on which primaquine is also active. Full assessment of the in vivo transmission-blocking activity of imidazoquines, in vitro tissue-schizontocidal activity on P. berghei-infected hepatocytes, and in vitro anti-P. carinii activity is now reported. All compounds were active in these biological assays, with generally lower activity than the parent drug. However, imidazoquines’ stability against both oxidative deamination and proteolytic degradation suggest that they will probably have higher oral bioavailability and lower hematotoxicity than primaquine, which might translate into higher therapeutic indexes.

a b s t r a c tThe synthesis of imidazolidin-4-one derivatives of primaquine containing the five-membered ring at the C-terminus of a dipeptide backbone coupled to the parent drug is described. These peptidomimetic derivatives were active against a chloroquine-resistant Plasmodium falciparum strain and inhibited the development of the sporogonic cycle of Plasmodium berghei, affecting the appearance of oocysts in the midguts of the mosquitoes. The novel imidazolidin-4-ones are extremely stable, both in human plasma and in pH 7.4 buffer, as a result of N 1 -acylation. Thus, 'internal' imidazolidin-4-ones derived from dipeptidyl 8-aminoquinolines represent a new entry in antimalarial structure-activity relationships.Ó 2008 Elsevier Ltd. All rights reserved.Primaquine, 1, is the only currently available drug that is active against both the latent liver forms of the relapsing malaria caused by Plasmodium vivax and Plasmodium ovale and the gametocytes from all species of parasite causing human malaria. 1 However, primaquine presents a short plasma half-life (ca. 6 h), 2 presumably due to its rapid oxidative deamination to carboxyprimaquine 2. [3][4][5] Blood toxicity, in particular hemolysis secondary to the ability of primaquine to induce oxidation of oxyhemoglobin to methemoglobin, has also been a source of concern. 6 Peptide and amino acid derivatives of primaquine have been prepared to reduce toxicity of the parent drug as well as to suppress the metabolic pathway leading to 2, 7-10 but many of these derivatives are rapidly hydrolyzed to primaquine by aminopeptidases and endopeptidases. 8,10 Imidazolidin-4-one formation is often used to protect the N-terminal amino acid residue of peptides and peptidomimetics. 11,12 Recently, we prepared imidazolidin-4-ones, 3, as potential peptidase-stable prodrugs of amino acid derivatives of primaquine. [13][14][15] Compounds 3 displayed gametocytocidal activity against Plasmodium berghei comparable to that of primaquine, as well as activity against P. falciparum asexual stages, while presenting high stability in pH 7.4 buffer (half-lives for hydrolysis typically higher than 12 h). 14, 16 We now set out to incorporate the imidazolidin-4-one moiety into dipeptide derivatives of primaquine, for example, 5 (Scheme 1), both to (i) introduce a terminal basic amino group reported as relevant for activity, 17 and (ii) effectively suppress hydrolysis of the imidazolidin-4-one due to acylation of the N 1 nitrogen atom. We herein report the synthesis and evaluation of the antiplasmodial activity of imidazolidin-4-ones 5 (Scheme 1). Compounds 5 were prepared as depicted in Scheme 1. a-Aminoacyl derivatives of primaquine, 4, were converted into the corresponding imidazolidin-4-ones 3 by refluxing with propanone, cyclopentanone, or cyclohexanone in MeOH. 18 Preliminary condensation of 3 with N-Boc-protected amino acids (BocAAOH) using 0960-894X/$ -see front matter Ó

Although drugs currently used for the various types of diseases (e.g., antiparasitic, antiviral, antibacterial, etc.) are effective, they present several undesirable pharmacological and pharmaceutical properties. Most of the drugs have low bioavailability, lack of sensitivity, and do not target only the damaged cells, thus also affecting normal cells. Moreover, there is the risk of developing resistance against drugs upon chronic treatment. Consequently, their potential clinical applications might be limited and therefore, it is mandatory to find strategies that improve those properties of therapeutic agents. The development of prodrugs using amino acids as moieties has resulted in improvements in several properties, namely increased bioavailability, decreased toxicity of the parent drug, accurate delivery to target tissues or organs, and prevention of fast metabolism. Herein, we provide an overview of models currently in use of prodrug design with amino acids. Furthermore, we review the challenges related to the permeability of poorly absorbed drugs and transport and deliver on target organs.