Thiosemicarbazone and thiazole: in vitro evaluation of leishmanicidal and ultrastructural activity on Leishmania infantum

• Published in: Medicinal chemistry research Vol. 29; no. 11; pp. 2050 - 2065
• Main Authors: Queiroz, Camila Marques, de Oliveira Filho, Gevanio Bezerra, Espíndola, José Wanderlan Pontes, do Nascimento, Amanda Vasconcelos, Aliança, Amanda Silva dos Santos, de Lorena, Virginia Maria Barros, Feitosa, Ana Paula Sampaio, da Silva, Paula Roberta, Alves, Luiz Carlos, Leite, Ana Cristina Lima, Brayner, Fábio André
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.11.2020; Springer Nature B.V
• Subjects: Amastigotes; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Cell body; Cytoplasm; Cytotoxicity; Depolarization; Developing countries; Flagella; Inorganic Chemistry; LDCs; Leishmania infantum; Macrophages; Mammalian cells; Medicinal Chemistry; Mitochondria; Nitric oxide; Original Research; Parasitic diseases; Peritoneum; Pharmacology/Toxicology; Spleen; Toxicity; Tropical diseases; Visceral leishmaniasis; Thiosemicarbazone; Amastigotes; Visceral Leishmaniasis; Ultrastructure; Thiazole
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-020-02619-z

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% (IC 50 ) against promastigote forms varied from 8.62 to 34.36 µM. In the evaluation of cytotoxicity, values of CC 50 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 CC 50 (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.