Development of new derivatives of primaquine by association with lysosomotropic carriers.

On the basis of the drug-carrier concept of chemotherapy, we entrapped primaquine in liposomes, and linked it to an amino acid (leucine), and to peptides (alanyl-leucine and alanyl-leucyl-alanyl-leucyl) as intermediate steps in the synthesis of covalent primaquine-glycoprotein conjugates that would be selectively recognized by hepatocytes.The therapeutic activity of these compounds was tested in mice infected with sporozoites of Plasmodium berghei. Causal prophylatic cures were obtained after a single intravenous injection of primaquine-liposomes (60-70 mg of primaquine/kg of bodyweight) and lower doses (35 mg of primaquine/kg of bodyweight) of ala-leu-primaquine and ala-leu-ala-leu-primaquine.The administration of such high doses was only possible as a result of the decreased toxicity of primaquine when entrapped in liposomes and confirms the validity of the drug-carrier concept for the treatment of malarial infections. The improved chemotherapeutic index of ala-leu-primaquine and ala-leu-ala-leu-primaquine resulted from their decreased toxicity and increased chemotherapeutic activity. These peptide derivatives are probably acting as pro-drugs of primaquine.