Identification of a Benzenesulfonylpiperazine Derivative With In Vivo Efficacy Against Visceral Leishmaniasis

Abstract

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.