Synthesis of α,γ-disubstituted-β-hydroxy-γ-lactones and evaluation of their anti-trypanosomatid activities.

Diseases caused by Leishmania spp. and Trypanosoma spp. parasites provoke thousands of annual deaths. The current treatments exhibit noticeable disadvantages such as low effectiveness, high cost, side-effects, and the occurrence of resistance. Thus, the search for new drugs is mandatory, and diversity-oriented synthesis appears as a useful tool to access libraries of small, structurally diverse, and potentially bioactive compounds in few steps. In this work, a battery of 10 new and highly substituted β-hydroxy-γ-lactones was straightforwardly synthesized from β,γ-unsaturated N-acyl oxazolidin-2-ones and evaluated against Leishmania amazonensis and Trypanosoma cruzi. Six of the compounds were found to exhibit antiparasitic activity against T. cruzi epimastigotes and/or L. amazonensis promastigotes, as well as against the amastigote forms of both parasites; among these, two compounds stood out against L. amazonensis, with selectivity indices (SI) higher than that of the reference drug. Furthermore, these two compounds appear to induce apoptosis-like cell death in L. amazonensis, as suggested by mechanistic studies. It is worth noting that the compound SAM-2 exhibited an SI four times higher than miltefosine, due to its lower toxicity compared to this drug, highlighting its potential as a promising candidate for the development of new therapies.