Development of new derivatives of primaquine by association with lysosomotropic carriers

摘要

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.