Diversity-oriented synthesis probe targets Plasmodium falciparum cytochrome b ubiquinone reduction site and synergizes with oxidation site inhibitors.

ABSTRACT:

Background

The emergence and spread of drug resistance to current antimalarial therapies remains a pressing concern, escalating the need for compounds that demonstrate novel modes of action. Diversity-Oriented Synthesis (DOS) libraries bridge the gap between conventional small molecule and natural product libraries, allowing the interrogation of more diverse chemical space in efforts to identify probes of novel parasite pathways.

Methods

We screened and optimized a probe from a DOS library using whole-cell phenotypic assays. Resistance selection and whole-genome sequencing approaches were employed to identify the cellular target of the compounds.

Results

We identified a novel macrocyclic inhibitor of Plasmodium falciparum with nanomolar potency and identified the redu

SUBMITTER: Lukens AK 

PROVIDER: S-EPMC4354981 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature