Evaluation of α,β-unsaturated ketones as antileishmanial agents

Abstract

In this study, we assessed the antileishmanial activity of 126 α,β-unsaturated ketones. The compounds NC901, NC884, and NC2459 showed high leishmanicidal activity for both the extracellular (50% effective concentration [EC50], 456 nM, 1,122 nM, and 20 nM, respectively) and intracellular (EC50, 1,870 nM, 937 nM, and 625 nM, respectively) forms of Leishmania major propagated in macrophages, with little or no toxicity to mammalian cells. Bioluminescent imaging of parasite replication showed that all three compounds reduced the parasite burden in the murine model, with no apparent toxicity.

FIG 1

In vivo activity of compounds NC901, NC884, and NC2459 in the murine model of CL. (A and B) Footpad size of BALB/c mice infected with 10⁵ and 10⁶ L. major metacyclic promastigotes, respectively. The Rx1 line refers to the time period in which treatment was administered daily, and the Rx2 line indicates that the daily dosage of NC2459 was doubled for that time period. (C) Luminescence of BALB/c mice footpads at 46 days postinfection with 10⁵ metacyclic promastigotes. *, P < 0.05. (D) Luminescence of BALB/c mice footpads at 29 days postinfection with 10⁶ metacyclic promastigotes. C, group treated with vehicle control; CD, group treated with amphotericin B. A statistical analysis of the net intensity (luminescence) of both the 10⁵ and 10⁶ experiments was carried out using the two-sided unpaired t test. *, P ≤ 0.05; **, P ≤ 0.01.