Identification of a Benzenesulfonylpiperazine Derivative With In Vivo Efficacy Against Visceral Leishmaniasis
Thibault Joseph William Jacques Dit Lapierre, Mariza Gabriela Faleiro de Moura Lodi Cruz, Guilherme Freitas de Lima Hercos, Rafael Consolin Chelucci, Simone Michelan‐Duarte, Gisele Barbosa, Analu R. Costa, Miguel Angel Chávez‐Fumagalli, Paula Derksen Macruz, Eduardo Jorge Pilau, Leonardo L. G. Ferreira, Adriano D. Andricopulo, Silvane Maria Fonseca Murta, Celso de Oliveira Rezende JúniorABSTRACT
Benzenesulfonylpiperazines have been previously identified as a promising class against Chagas disease and leishmaniasis, two parasitic neglected tropical diseases. Thus, the pharmacokinetic profile of two potential leads against visceral leishmaniasis was assessed in vitro. Both lead candidates 1 and 2 exhibited a satisfactory ADME profile, with 2 proving slightly superior in terms of metabolic stability. Therefore, after complementary toxicity assessment which revealed that 2 did not exert hepatotoxicity in vitro or acute toxicity in vivo, the evaluation of its efficacy in a mouse model highlighted that 2 indeed displays antileishmanial efficacy in vivo. Albeit moderate at a dose of 50 mg/kg/day, its efficacy increased at a dose of 100 mg/kg/day, reducing the parasite burden by 90% in the spleen of infected mice, though safety concerns were raised at this dose. In vitro investigation of its mode of action revealed that 2 exerts a cytostatic effect on Leishmania infantum promastigotes, promoting cell cycle arrest during the G0/G1 phase which may potentially be linked to the production of reactive oxygen species.