Journal article
Discovery, Synthesis, and Optimization of Antimalarial 4(1H)-Quinolone-3-Diarylethers
Journal of medicinal chemistry, v 57(9), pp 3818-3834
08 May 2014
PMID: 24720377
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The
historical antimalarial compound endochin served as a structural lead
for optimization. Endochin-like quinolones (ELQ) were prepared by
a novel chemical route and assessed for in vitro activity against
multidrug resistant strains of
Plasmodium falciparum
and against malaria infections in mice. Here we describe the pathway
to discovery of a potent class of orally active antimalarial 4(1
H
)-quinolone-3-diarylethers. The initial prototype, ELQ-233,
exhibited low nanomolar IC
50
values against all tested
strains including clinical isolates harboring resistance to atovaquone.
ELQ-271 represented the next critical step in the iterative optimization
process, as it was stable to metabolism and highly effective in vivo.
Continued analoging revealed that the substitution pattern on the
benzenoid ring of the quinolone core significantly influenced reactivity
with the host enzyme. This finding led to the rational design of highly
selective ELQs with outstanding oral efficacy against murine malaria
that is superior to established antimalarials chloroquine and atovaquone.
Metrics
Details
- Title
- Discovery, Synthesis, and Optimization of Antimalarial 4(1H)-Quinolone-3-Diarylethers
- Creators
- Aaron Nilsen - , 3710 SW US Veterans Hospital Road, Portland, Oregon 97239Galen P Miley - , 3710 SW US Veterans Hospital Road, Portland, Oregon 97239Isaac P Forquer - , 3710 SW US Veterans Hospital Road, Portland, Oregon 97239Michael W Mather - Department of Microbiology and ImmunologyKasiram Katneni - Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical SciencesYuexin Li - , 3710 SW US Veterans Hospital Road, Portland, Oregon 97239Sovitj Pou - , 3710 SW US Veterans Hospital Road, Portland, Oregon 97239April M Pershing - Department of Microbiology and ImmunologyAllison M Stickles - Department of Physiology and PharmacologyEileen Ryan - Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical SciencesJane Xu Kelly - , 3710 SW US Veterans Hospital Road, Portland, Oregon 97239J. Stone Doggett - , 3710 SW US Veterans Hospital Road, Portland, Oregon 97239Karen L White - Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical SciencesDavid J Hinrichs - , 3710 SW US Veterans Hospital Road, Portland, Oregon 97239Rolf W Winter - , 3710 SW US Veterans Hospital Road, Portland, Oregon 97239Susan A Charman - Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical SciencesLev N Zakharov - Department of ChemistryIan Bathurst - , 20 route de Pré-Bois, PO Box 1826, 1215 Geneva 15Jeremy N Burrows - , 20 route de Pré-Bois, PO Box 1826, 1215 Geneva 15Akhil B Vaidya - Department of Microbiology and ImmunologyMichael K Riscoe - , 3710 SW US Veterans Hospital Road, Portland, Oregon 97239
- Publication Details
- Journal of medicinal chemistry, v 57(9), pp 3818-3834
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000335879100017
- Scopus ID
- 2-s2.0-84900336048
- Other Identifier
- 991014878644904721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal