Project Summary
Malaria transmission occurs through the bite of Plasmodium-infected mosquitoes of the genus Anopheles, and
in much of sub-Saharan Africa, transmission of the deadliest Plasmodium falciparum parasites is mediated by
the sibling mosquito species Anopheles gambiae and An. coluzzii. The best method available to prevent malaria
infection is through long-lasting insecticide impregnated mosquito bed nets (LLINs). Distribution of LLINs has
had a massive impact on the number of malaria cases, particularly in sub-Saharan Africa, with epidemiological
modelling predicting that between 2000 and 2015 LLINs were responsible for as much as 68% of the observed
reduction in malaria cases in this period (1). As such, insecticide-based mosquito control represents the
cornerstone of malaria prevention and elimination efforts. Inevitably, however, mass distribution of LLINs has
driven widespread resistance to pyrethroid insecticides in Anopheles populations. This issue stresses the need
for new tools to prevent malaria transmission. We recently demonstrated that antimalarials applied to solid
surfaces can kill the mosquito stages of P. falciparum parasites when Anopheles females absorb these
compounds via their legs. From a preliminary in vivo efficacy screen, we have identified two structurally similar
endoquine-like quinolone (ELQ) compounds that very efficiently target different sites (Qo and Qi, which
importantly do not induce cross-resistance) on the P. falciparum cytochrome bc1 complex. These compounds,
ELQ-453 (Qo) and ELQ-613 (Qi), exhibit outstanding performance in our in vivo tarsal contact transmission
blocking assay. Here we propose to build on the structural backbone of these compounds and use an iterative
medicinal chemistry approach to optimize both potency against mosquito stages of parasite development and
efficiency of tarsal uptake. Furthermore, we will determine the activity of compounds after impregnation in bed
net-like polymer fiber textiles that will allow testing for durability, photostability, wash-resistance and other
parameters essential for the development of an antimalarial-coated bed net product destined for use in malaria-
endemic areas. Specifically, we will: Aim 1) Design ELQ compounds with increased anti-parasitic potency by
varying their constituent 3-alkyl side chain and benzenoid substituents. We will also investigate the propensity
of the best-performing compounds to select resistant parasite mutants, and will test transmissibility of these
mutants to mosquitoes; Aim 2) Maximize tarsal availability and mosquito pharmacokinetics of these novel ELQ
compounds by optimizing the design of their prodrug moiety; Aim 3) Develop and validate novel ELQ-
impregnated textiles as a prototype for future bed net products incorporating both insecticide and antimalarial
ingredients. To achieve these goals, we will collaborate with leaders in the fields of ELQ medicinal chemistry
(Mike Riscoe OHSU), and product development and testing (Mike Rubal, SwRI). At the end of this project, we
will have generated and validated an innovative mosquito-targeting control tool to reduce malaria transmission
and limit the impact of insecticide resistance.
