Abstract
Leishmaniasis is a much-neglected tropical disease, especially in developing countries. Visceral Leishmaniasis (VL) is the most severe form of this infection caused by Leishmania infantum specie. It affects the splenic and hepatic systems and, when left untreated, it is fatal in 95% of cases. There is no human vaccine available and the recommended treatment not only presents adverse effects but it enables the development of resistant strains if interrupted. Hence, the urgent search for new leishmanicidal compounds. In the present work, we evaluated the in vitro leishmanicidal action of new thiosemicarbazone and thiazolidine compounds against the evolutionary forms of L. infantum, as well as their hemolytic activity, ultrastructural alterations, cytotoxicity, and nitric oxide levels on peritoneal macrophages. The inhibitory concentration 50% (IC50) against promastigote forms varied from 8.62 to 34.36 µM. In the evaluation of cytotoxicity, values of CC50 in peritoneal macrophages varied from 31.80 to 196.38 µM. Data showed that compounds JW-16.2 and GT-14 were the most promising in the series as they displayed the highest CC50 (184.58 and 196.38 μM), SI (19 and 15), low hemolytic activity, induced NO production in uninfected and infected macrophages and reduced survival of amastigotes (24.39 and 16.51 μM). Ultrastructural alterations, such as shrinkage of the cell body, shortening of the flagellum, and vacuolization of the cytoplasm, were identified. Promastigote forms treated with compounds GT-14 showed depolarization of mitochondria. Therefore, both compounds are promising due to low cytotoxicity to mammalian cells and leishmanicidal action.
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Acknowledgements
The authors would like to acknowledge Gabriel Gazzoni and Jana Sandes for the scientific and operational support provided. This work has been carried out with the support of the Co-ordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brazil (CAPES) and Oswaldo Cruz Foundation (Fiocruz-Pernambuco)—Brazil.
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This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) and PROEP FIOCRUZ/CNPq, process number 400629/2019-4.
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Queiroz, C.M., de Oliveira Filho, G.B., Espíndola, J.W.P. et al. Thiosemicarbazone and thiazole: in vitro evaluation of leishmanicidal and ultrastructural activity on Leishmania infantum. Med Chem Res 29, 2050–2065 (2020). https://doi.org/10.1007/s00044-020-02619-z
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DOI: https://doi.org/10.1007/s00044-020-02619-z