Synthesis and in vitro evaluation of potential anti-leishmanial targeted drugs of pyrimethamine.

Pyrimethamine, an antimalarial drug, was found to be able to inhibit both enzymes (DHFR-TS and PTR1) of the leishmanial folate pathway, although this effect in vivo appears only in relatively high concentrations. To reach the parasites inside macrophage cells, where they are sheltered, targeted drugs of pyrimethamine, carboxymethyldextran-thiomannopyranoside-pyrimethamine (CMD-P), and succinyldextran-thiomannopyranoside-pyrimethamine (SD-P), were synthesized and assayed against L.(L.) amazonensis amastigotes. CMD-P has 2.43% and SD-P has 2.58% of pyrimethamine attached. At a CMD-P dose of 200 microg/mL (4.86 microg/mL pyrimethamine), the results were very promising, with a destruction of approximately 50% of the intracellular amastigotes, with no detectable toxicity to macrophage cells. SD-P in similar doses did not show good results, probably due to different patterns of drug release. These results open the possibility of treating leishmaniasis with a safe targeted drug of pyrimethamine released directly inside the macrophage cells, reducing the host systemic toxicity. Copyright 2003 Wiley-Liss, Inc. and the American Pharmacists Association