Tetraoxanes as new agents against Leishmania amazonensis

Leishmaniasis is a neglected disease, caused by a parasite of Leishmania genus and widespread in the tropical and subtropical areas of the world. Currents drugs are limited due to their toxicity and parasite resistance. Therefore, the discovery of new treatment, more effective and less toxic, is urgent. In this study we report the synthesis of six gem -dihydroperoxides ( 2a-f ), with yields ranging from 10% to 90%, utilizing a new methodology. The dihydroperoxides were converted into ten tetraoxanes ( 3a-j ), among which six ( 3b , 3c , 3d , 3g , 3h and 3j ) showed activity against intracellular amastigotes of Leishmania amazonensis. The cytotoxicity of all compounds was also evaluated against canine macrophages (DH82), human hepatoma (HepG2) and monkey renal cells (BGM). Most compounds were more active and less toxic than potassium antimonyl tartrate trihydrate, used as positive control. Amongst all tetraoxanes, 3b (IC 50 = 0.64 microM) was the most active, being more selective than positive control in relation to DH82, HepG2 and BGM cells. In summary, the results revealed a hit compound for the development of new drugs to treat leishmaniasis.