jm500942v_si_001.pdf (4.44 MB)
Orally Bioavailable 6‑Chloro-7-methoxy-4(1H)‑quinolones Efficacious against Multiple Stages of Plasmodium
journal contribution
posted on 2015-12-17, 05:48 authored by R. Matthew Cross, David L. Flanigan, Andrii Monastyrskyi, Alexis N. LaCrue, Fabián E. Sáenz, Jordany R. Maignan, Tina S. Mutka, Karen
L. White, David M. Shackleford, Ian Bathurst, Frank R Fronczek, Lukasz Wojtas, Wayne
C. Guida, Susan A. Charman, Jeremy N. Burrows, Dennis E. Kyle, Roman ManetschThe continued proliferation
of malaria throughout temperate and
tropical regions of the world has promoted a push for more efficacious
treatments to combat the disease. Unfortunately, more recent remedies
such as artemisinin combination therapies have been rendered less
effective due to developing parasite resistance, and new drugs are
required that target the parasite in the liver to support the disease
elimination efforts. Research was initiated to revisit antimalarials
developed in the 1940s and 1960s that were deemed unsuitable for use
as therapeutic agents as a result of poor understanding of both physicochemical
properties and parasitology. Structure–activity and structure–property
relationship studies were conducted to generate a set of compounds
with the general 6-chloro-7-methoxy-2-methyl-4(1H)-quinolone scaffold which were substituted at the 3-position with
a variety of phenyl moieties possessing various properties. Extensive
physicochemical evaluation of the quinolone series was carried out
to downselect the most promising 4(1H)-quinolones, 7, 62, 66, and 67,
which possessed low-nanomolar EC50 values against W2 and
TM90-C2B as well as improved microsomal stability. Additionally, in
vivo Thompson test results using Plasmodium berghei in mice showed that these 4(1H)-quinolones were
efficacious for the reduction of parasitemia at >99% after 6 days.
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PlasmodiumThestabilityquinolone seriesremedyOrallytherapycompoundworldW 2malariadownselectscaffoldresearchparasitologyproliferationartemisinin combination therapiesPlasmodium bergheiECunderstandingvivo Thompson test resultsBioavailableMultiple StagesChloroExtensive physicochemical evaluationrelationshipparasitemiaparasite resistancephenyl moietiesregionagentphysicochemical propertiesvariety6 daysTMEfficacioucombatchlorodisease elimination effortsantimalarial
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