Tolnaftate inhibits ergosterol production and impacts cell viability of Leishmania sp.

Author(s)

Yamamoto, Eduardo Seiji ^[1] ; de Jesus, Jessica Adriana ^[1] ; Bezerra-Souza, Adriana ^[1] ; Brito, Juliana R. ^[2] ; Lago, Joao Henrique G. ^[2] ; Laurenti, Marcia Dalastra ^[1] ; Passero, Luiz Felipe Domingues ^{[3, 4]}

Affiliation

^[1] Univ Sao Paulo, Sch Med, Dept Pathol, Lab Pathol Infect Dis LIM50, Ave Dr Arnaldo, 455, BR-01246903 Sao Paulo, SP - Brazil

^[2] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210180 Sao Paulo, SP - Brazil

^[3] Sao Paulo State Univ UNESP, Inst Biosci, Praca Infante Dom Henrique, S-N, BR-11330900 Sao Vicente, SP - Brazil

^[4] Sao Paulo State Univ UNESP, Inst Adv Studies Ocean, Ave Joao Francisco Bensdorp, 1178, BR-11350011 Sao Vicente, SP - Brazil

• Document type: Journal article
• Source: BIOORGANIC CHEMISTRY; v. 102, SEP 2020.
• Web of Science Citations: 2

Abstract

Leishmaniasis is an infectious disease caused by protozoan parasites of the genus Leishmania. The treatment of all forms of leishmaniasis relies on first-line drug, pentavalent antimonial, and in cases of drug failure, the second-line drug amphotericin B has been used. Besides the high toxicity of drugs, parasites can be resistant to antimonial in some areas of the World, making it necessary to perform further studies for the characterization of new antileishmanial agents. Thus, the aim of the present work was to evaluate the leishmanicidal activity of tolnaftate, a selective reversible and non-competitive inhibitor of the fungal enzyme squalene epoxidase, which is involved in the biosynthesis of ergosterol, essential to maintain membrane physiology in fungi as well as trypanosomatids. Tolnaftate eliminated promastigote forms of L. (L.) amazonensis, L. (V.) braziliensis and L. (L.) infantum (EC50 similar to 10 mu g/mL and SI similar to 20 for all leishmanial species), and intracellular amastigote forms of all studied species (EC50 similar to 23 mu g/mL in infections caused by dermatotropic species; and 11.7 mu g/mL in infection caused by viscerotropic species) with high selectivity toward parasites {[}SI similar to 8 in infections caused by dermatotropic species and 17.4 for viscerotropic specie]. Promastigote forms of L. (L.) amazonensis treated with the EC50 of tolnaftate displayed morphological and physiological changes in the mitochondria and cell membrane. Additionally, promastigote forms treated with tolnaftate EC50 reduced the level of ergosterol by 5.6 times in comparison to the control parasites. Altogether, these results suggest that tolnaftate has leishmanicidal activity towards Leishmania sp., is selective, affects the cell membrane and mitochondria of parasites and, moreover, inhibits ergosterol production in L. (L.) amazonensis. (AU)

• FAPESP's process: 15/17623-6 - Evaluation of the Leishmanicidal Potential from Drugs which Act in the Sterols Biochemical Pathway
• Grantee: Eduardo Seiji Yamamoto
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 18/07885-1 - Biomolecules from plant species of remnant areas of the Atlantic Forest and Cerrado to treat neglected tropical diseases - chemical and pharmacological aspects
• Grantee: João Henrique Ghilardi Lago
• Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants
• FAPESP's process: 16/00468-0 - Use of drug repurposing and natural product bioprospection to characterize compounds with in vitro and in vivo leishmanicidal action
• Grantee: Luiz Felipe Domingues Passero
• Support Opportunities: Regular Research Grants