In vitro leishmanicidal activity of two cholesterol derivatives

Area of Science:

• * Parasitology and Tropical Medicine
• * Drug Discovery and Development

Background:

• * Leishmaniasis remains a significant global health concern, particularly cutaneous leishmaniasis.
• * Current treatments, like sodium stibogluconate (Sb), face challenges including toxicity and resistance.
• * Sterols are essential components of cell membranes and potential targets for antiparasitic agents.

Purpose of the Study:

• * To evaluate the leishmanicidal activity of 5α-cholest-7-en-3β-ol (5α-chol) and (+)-4-cholesten-3-one ((+)-4-chol), individually and as an equimolar mixture.
• * To assess the synergistic effects and therapeutic potential of these sterols against Leishmania mexicana.
• * To determine the cytotoxicity of the sterols on host macrophages.

Main Methods:

• * Leishmanicidal activity assessed against promastigotes and amastigotes of Leishmania mexicana (LCL and DCL strains).
• * Parasite viability and proliferation evaluated using propidium iodide and CFSE staining.
• * Cytotoxicity determined by trypan blue exclusion assay in macrophages; compared with sodium stibogluconate (Sb) and DMSO controls.

Main Results:

• * The equimolar mixture of 5α-chol and (+)-4-chol exhibited significant leishmanicidal activity, comparable to Sb at 2000x lower concentration.
• * The mixture demonstrated synergistic effects, being 100x more effective than individual sterols against LCL and DCL parasites.
• * The sterol mixture showed a therapeutic index 10,000-16,000 times higher than Sb and was non-cytotoxic to macrophages.

Conclusions:

• * The equimolar mixture of 5α-chol and (+)-4-chol possesses potent synergistic leishmanicidal activity.
• * This sterol combination presents a promising, non-toxic alternative for treating cutaneous leishmaniasis.
• * Further investigation into this sterol mixture as a therapeutic agent is warranted.