Seite - (000234) - in Biomedical Chemistry: Current Trends and Developments

Figure 3.1.9: Structures do PQ and its imidazolidin-4-ones derived from L-amino acids and carbonyl compounds. This research group incorporated the imidazolidin-4-one moiety into dipeptide derivatives of PQ (7, Fig. 3.1.9), both to introduce a terminal basic amino group reported as relevant for activity, and effectively suppress hydrolysis of the imidazolidin-4-one through acylation of the N1 nitrogen atom (Vale, 2008b; 2008c). These peptidomimetic derivatives were active against a chloroquine-resistant P. falciparum strain and inhibited the development of the sporogonic cycle of P. berghei, affecting the appearance of oocysts in the midguts of the mosquitoes and were extremely stable, both in human plasma and in pH 7.4 buffer as a result of N1-acylation (Vale, 2008b). All compounds were also active in many biological assays (in vivo transmission-blocking activity, in vitro tissue-schizontocidal activity on P. berghei infected hepatocytes and in vitro anti-P. carinii activity), with generally lower activity than the parent drug. However, these imidazoquines are stable compounds because of blockage of the aliphatic amine of PQ by insertion of the peptidomimetic carrier. Structure 7 compounds are not vulnerable to oxidative deamination, which is the main metabolic process behind the low oral bioavailability of PQ. On the other hand, the use of a peptidomimetic instead of a dipeptide carrier makes compound 7 stable to proteolytic degradation by action of amino- or endopeptidases (Vale, 2009b).