Seite - (000231) - in Biomedical Chemistry: Current Trends and Developments

3.1.2.4. Variability of Amino Acid Application to Exclusive Drugs Primaquine (PQ, 4, Fig. 3.1.9) is the only generally available anti- malarial that prevents relapse in vivax and ovale malaria, and is the only potent gametocytocide in falciparum malaria. Primaquine becomes increasingly important as malaria-endemic countries move towards elimination, and although it is widely recommended, it is commonly not given to malaria patients because of haemolytic toxicity in subjects who are glucose-6-phosphate dehydrogenase (G6PD) deficient (gene frequency typically 3−30% in malaria endemic areas; > 180 different genetic variants) (Ashley, 2014). PQ is often associated with serious adverse effects because of its toxic metabolites (Vale, 2009). Blocking the terminal primary amine in PQ may represent a huge improvement in terms of PQ bioavailability, as it can significantly reduce the extent of PQ conversion into carboxyPQ, the principal metabolite. N-Acylation of anti-malarials with amino acids and oligopeptides has been used in several works aimed at improving drug transport into malaria-infected erythrocytes and over the last two decades, these modifications started to be also seen as a means to avoid premature PQ inactivation by oxidative deamination to carboxyPQ (Kirk, 2001). An earlier work describes the synthesis of N-cysteinyl-PQ that was subsequently coupled to carrier proteins, and both the anti-malarial activity in vivo and the acute lethal toxicity of the protein-drug conjugates were evaluated. The causal prophylactic activity of the lactosaminated serum albumin conjugate was two times higher than that of the free drug, whereas its acute lethal toxicity was at least 6.5-fold lower than that of PQ [mean lethal dose (LD50) > 85 mg of PQ base kg-1]. This yielded a therapeutic index for the conjugate at least 12 times higher than that of the free parent drug (Hofsteenge, 1986). Oligopeptide derivatives of PQ such as PQ-Lys-Leu-d-Val, PQ-Lys- Leu-Ala and PQ-Lys-Leu-l-Val have been prepared and tested for radical curative anti-malarial activity against P. cynomolgi in rhesus monkeys and blood-schizontocidal activity against P. berghei in mice. The d-Val- containing derivative was found to be less toxic and more active than both its l-Val counterpart and PQ, whereas the activity of the Ala- bearing compound was comparable to that of the l-Val derivative