4-Chlorophenylthioacetone-derived thiosemicarbazones as potent antitrypanosomal drug candidates: Investigations on the mode of action.
Chagas disease (ChD), caused by Trypanosoma cruzi, remains a challenge for the medical and scientific fields due to the inefficiency of the therapeutic approaches available for its treatment. Thiosemicarbazones and hydrazones present a wide spectrum of bioactivities and are considered a platform for the design of new anti-T. cruzi drug candidates. Herein, the potential antichagasic activities of [(E)-2-(1-(4-chlorophenylthio)propan-2-ylidene)-hydrazinecarbothioamides] (C1, C3), [(E)-N'-(1-((4-chlorophenyl)thio)propan-2-ylidene)benzohydrazide] (C2), [(E)-2-(1-(4-, and [(E)-2-(1-((4-chlorophenyl)thio)propan-2-ylidene)hydrazinecarboxamide] (C4) were investigated. Macrophages (MOs) from C57BL/6 mice stimulated with C1 and C3, but not with C2 and C4, reduced amastigote replication and trypomastigote release, independent of nitric oxide (NO) and reactive oxygen species production and indoleamine 2,3-dioxygenase activity. C3, but not C1, reduced parasite uptake by MOs and potentiated TNF production. In cardiomyocytes, C3 reduced trypomastigote release independently of NO, TNF, and IL-6 production. C1 and C3 were non-toxic to the host cells. A reduction of parasite release was found during infection of MOs with trypomastigotes pre-incubated with C1 or C3 and MOs pre-stimulated with compounds before infection. Moreover, C1 and C3 acted directly on trypomastigotes, killing them faster than Benznidazole, and inhibited T. cruzi proliferation at various stages of its intracellular cycle. Mechanistically, C1 and C3 inhibit parasite duplication, and this process cannot be reversed by inhibiting the DNA damage response. In vivo, C1 and C3 attenuated parasitemia in T. cruzi-infected mice. Moreover, C3 loaded in a lipid nanocarrier system (nanoemulsion) maintained anti-T. cruzi activity in vivo. Collectively, these data suggest that C1 and C3 are candidates for the treatment of ChD and present activity in both the host and parasite cells.
['Rodney Rodrigues de Assis|Diego|D|', 'Almeida Oliveira|Alexandre|A|', 'Luiz Porto|Samuel|S|', 'Aparecida Nonato Rabelo|Rayane|R|', 'Burgarelli Lages|Eduardo|E|', 'Corrêa Santos|Viviane|V|', 'Marques Milagre|Matheus|M|', 'Perdigão Fragoso|Stenio|S|', 'Martins Teixeira|Mauro|M|', 'Salgado Ferreira|Rafaela|R|', 'Renato Machado|Carlos|C|', 'Antônio Miranda Ferreira|Lucas|L|', 'Lucio Speziali|Nivaldo|N|', 'Beraldo|Heloisa|H|', 'Simão Machado|Fabiana|F|']
D000818:Animals D002470:Cell Survival D014355:Chagas Disease D003546:Cysteine Endopeptidases D016207:Cytokines D004195:Disease Models, Animal D015195:Drug Design D005260:Female D008018:Life Cycle Stages D008264:Macrophages D051379:Mice D008810:Mice, Inbred C57BL D008968:Molecular Conformation D009569:Nitric Oxide D015800:Protozoan Proteins D051381:Rats D013882:Thiosemicarbazones D014344:Trypanocidal Agents D014349:Trypanosoma cruzi
Thiosemicarbazones Chagas disease Trypanosoma cruzi Treatment Hydrazones Lipid nanoparticles