Page - (000232) - in Biomedical Chemistry: Current Trends and Developments

(Philip, 1988). PQ N-acylation with amino acids or oligopeptides yields structures that are amenable to proteolytic degradation. Despite this bioreversibility being desirable in a prodrug, fast conversion into PQ will not overcome the problems associated with PQ-based therapies. Thus, additional protection of the peptide moiety in peptidyl-PQ compounds became a new goal so structures could be obtained with resistance to early proteolytic cleavage and bioreversibility at target tissues or cells to release the active molecule (Bundgaard and Moss, 1989). Two groups of tetrapeptides with general formula PQ-Y-Ala-Leu-X-NH2 were also synthesized. In the first group, Leu, Tyr, Lys and Asp were used in the Y positions and Ala at X. In the second group, Ala, Tyr, Lys and Asp were used in X positions, while Y was Leu. The peptide derivatives were then coupled to polyacryl starch microparticles (via the N-terminal amino acid α-amino group), forming lysosomotropic drug carriers (Borissova, 1995). Dipeptide derivatives of PQ (PQ-Arg-Phe, PQ-Arg-Lys and PQ-Ala- Phe) were also synthesized and tested against Chagas disease. PQ-Arg- Lys was seen to be active against T. cruzi development inside host cells, probably by interfering with the initial steps of trypomastigote- amastigote transformation. This derivative was more active than the other two, so it seems that specific cleavage has an important role in PQ release (Chung, 1997). Portela have also evaluated the dipeptide derivatives of PQ as novel transmission-blocking anti-malarials. In contrast with PQ, none of the compounds were able to block oocyst production in mosquitoes’ midguts at 3.75 mg kg-1 but all were found to completely inhibit the formation of oocysts at 15 mg kg-1, where N- acetylPQ is not active at this dose. As a whole, this work has demonstrated that acylation of the PQ’s primary amino group effectively prevents the early conversion of PQ into carboxyPQ while confirming that the presence of a terminal amino group, as in the dipeptide derivatives of PQ, is essential for gametocytocidal activity (Portela, 1999). Gomes worked on the further transformation of the amino acid moiety linked to the PQ primary amine with the introduction of an imidazolidin-4-one ring at the amino acid’s α-amino group (5, Fig. 3.1.9). Condensation of the N-aminoacyl derivatives of PQ with carbonyl compounds (ketones or aldehydes) was suggested by these authors as a