Nitro-Heterocyclic compounds induce apoptosis-like effects in Leishmania (L). amazonensis promastigotes

Author(s)

Dias Mendonca, Daiane Barros ^{[1, 2]} ; Costa Silva, Renata Ellen ^{[1, 2]} ; Palace-Berl, Fanny ^[3] ; Takakura, Cleusa F. H. ^[4] ; Soares, Sandra Regina C. ^[5] ; Almeida Braz, Lucia Maria ^{[1, 2]} ; Tavares, Leoberto Costa ^[3] ; Lauletta Lindoso, Jose Angelo ^{[1, 2, 6, 7]}

Affiliation

^[1] Univ Sao Paulo, Inst Trop Med, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Lab Serum Epidemiol, Fac Med, Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Dept Biochem Pharmaceut Technol, Lab Planning & Dev Pharmaceut, Fac Pharm, Sao Paulo, SP - Brazil

^[4] Univ Sao Paulo, Dept Pathol, Fac Med, Sao Paulo, SP - Brazil

^[5] Univ Sao Paulo, Inst Trop Med, Lab Protozool, Fac Med, Sao Paulo, SP - Brazil

^[6] Secretary State Hlth, Inst Infectol Emilio Ribas, Sao Paulo, SP - Brazil

^[7] Univ Brasilia, Ctr Trop Med, Fac Med, Brasilia, DF - Brazil

• Document type: Journal article
• Source: Journal of Venomous Animals and Toxins including Tropical Diseases; v. 25, MAR 11 2019.
• Web of Science Citations: 1

Abstract

Background: Three drugs - pentavalent antimonials, amphotericin B and pentamidine - are currently used for leishmaniasis treatment. They are administered for long periods, only parenterally, and have high cardiac, renal and hepatic toxicities. Therefore, the investigation of new compounds is required. Nitro-heterocyclic derivatives have been used as possible drug candidates to treat diseases caused by trypanosomatids. Methods: Leishmania (L.) amazonensis promastigotes (MHO/BR/73/M2269), maintained in the Laboratorio de Soroepidemiologia - Instituto de Medicina Tropical-USP, were exposed to five nitroheterocyclic derivatives, with differences at phenyl-ring position 4: BSF-C4H9, BSF-H, BSF-NO2, BSF-CH3 and BSF-Cl, for 48 hours. After analyzing viability (MTT assay), we evaluated cellular-morphology activity of compounds by transmission electron microscopy (TEM) and measurement of apoptosis (phosphatidylserine expression) by flow cytometry. Results: EC50 of amphotericin B and BSF-CH3 were 0.50 mu M and 0.39 mu M respective. Other nitro-heterocyclic compounds presented EC50 higher than amphotericin B. All compounds showed greater AV - and PI-positive expression than amphotericin B at 100 mu M, except BSF-NO2. TEM showed complete nuclear disfigurement with 100 mu M of BSF-NO2, 25 and 6.25 mu M of BSF-H, and 6.25 mu M BSF-Cl; presence of vesicles within the flagellar pocket with 25 mu M BSF-H; alteration of the kinetoplast with 25 mu M BSF-C4H9, 25 mu M of BSF-H, 6.25 mu M BSF-CH3 and 6.25 mu M of BSF-Cl. Conclusions: Nitro-heterocyclic compounds have shown activity against promastigotes of L. amazonensis, at lower concentrations. However, improvement of compound scaffolds are needed to assist the elucidation of the mechanism of action and to achieve greater activity. (AU)

• FAPESP's process: 14/06061-4 - Nitro-compounds with Trypanosoma cruzi activity: design, synthesis, evaluation of cytotoxicity and bioactivity in vitro and studies of structure-activity relationships in silico
• Grantee: Leoberto Costa Tavares
• Support type: Regular Research Grants