Leishmanicidal Activity of Novel Synthetic Furoxan and Benzofuroxan Derivatives

A novel series of furoxan (1,2,5-oxadiazole 2-oxide) (3, 4a–b, 13a-b and 14a-f) and benzofuroxan (benzo[c][1,2,5]oxadiazole 1-oxide) (7, 8a-c) derivatives were synthesized, characterized and evaluated for in vitro activity against promastigote and intracellular amastigote forms of Leishmania amazonensis. The furoxan derivatives exhibited ability to generate nitric oxide at different levels (7.8%-27.4%). The benzofuroxan derivative 8a was able to increase nitrite production in supernatants medium from murine macrophages infected with L. amazonensis at 0.75 mM after 48h. Furoxan and benzofuroxan derivatives showed remarkable leishmanicidal activity against both promastigote and intracellular amastigote forms. Compounds 8a, 14a-b and 14d exerted selective leishmanicidal activity superior to amphotericin B and pentamidine. In vitro studies in pH 5.4 reveals that compounds 8a is stable until 8 hours and compound 14a behave as a prodrug, releasing the active aldehyde 13a. These compounds have emerged as promising novel drug candidates for the treatment of leishmaniasis.