Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials

Abstract

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.

Figure 1.

Transition from first-generation acridones to the second-generation acridones.

Figure 2.

Bioluminescent and real-time in vivo imaging (IVIS) of parasite load in mice with and without acridone treatment. Mice were inoculated with 10000 luciferase-expressing P. berghei sporozoite intravenously (i.v.) on day 0 and oral doses of acridones were administered on day −1, day 0, and day 1. The bioluminescent level represents the parasite burden over the body surface area at 24, 48, and 72 h time points.

Figure 3.

Ex vivo activity of acridones and control antimalarial drugs against P. falciparum clinical isolates in Uganda. Data are presented as geometric means ± 95% CI. CQ: chloroquine; PIP: piperaquine; DHA: dihydroartemisinin; ATV: atovaquone; LUM: lumefantrine.

Scheme 1.

Synthesis of Acridones (18−58) with Aryloxy, Arylamino and Aryl Groups at the 6 Position of Ring-B^a

Scheme 2.

Synthesis of Acridones (68−80) with Aryloxy and Arylamino Groups at the 7 Position of Ring-B^a

Scheme 3.

Synthesis of Acridones (86−93, 99−102 and 107−109) with Benzyloxy Groups at the 6 Position (Top and Middle Panel) and the 7 Position (Bottom Panel) of the Ring-B^a