Seite - (000233) - in Biomedical Chemistry: Current Trends and Developments

means to protect the amino acid moiety against premature proteolytic degradation (Gomes, 2004). Imidazolidin-4-ones were highly stable in human plasma, with a weak or null degree of PQ release after 3 days of incubation. Moreover, compound 5 hydrolyzed 50-100 times slower in aqueous buffer at physiological pH and T than the corresponding imidazolidin-4-ones derived from di- and penta-peptides (Araújo, 2005; Chambel, 2006). These imidazolidin-4-ones (5) were effective in preventing P. berghei malaria transmission from BalbC mice to Anopheles stephensi mosquitoes (Araújo, 2005; Vale, 2005). Most of these compounds were also active against Pneumocystis carinii above 10 μg mL-1, which was correlated to their anti-P. falciparum blood- schizontocidal activity in vitro (Vale, 2008a). Later, PQ dipeptide derivatives bearing an imidazolidin-4-one moiety at the N-terminus (6, Fig. 3.1.9) were synthesized and evaluated as potential transmission-blocking antimalarial prodrugs. All compounds were hydrolyzed to the parent dipeptide derivative of PQ in neutral and basic solutions, with half-lives ranging from 0.7 to 31 h at 37°C, depending on the nature of the substituents present in the imidazolidin- 4-one moiety and in the C-terminal amino acid directly coupled to PQ. The imidazolidin-4-one derived from Ala-Ala-PQ and acetone reduced the transmission of the infection to mosquitoes more efficiently than PQ, as shown by the significant decrease in the number of oocysts in the midguts of the mosquitoes at 10 and 50 mmol kg-1 when compared to the control (Vale, 2009a). A recent report from the same authors provides the synthesis and biological activity of N1-aminoacyl derivatives of 5 (7, Fig. 3.1.9) as mimetics of PQProXaa structures (where Xaa represents a general amino acid). Such structures were again found to be remarkably stable, modestly active as a blood-schizontocidal against a CQ-resistant strain of P. falciparum and effective inhibitors of the sporogonic cycle of P. berghei in A. stephensi mosquitoes (Vale, 2008b).