Potent Antimalarial 2‑Pyrazolyl Quinolone bc1 (Qi) Inhibitors with Improved
Drug-like Properties
Version 3 2018-11-13, 15:06
Version 2 2018-11-07, 19:35
Version 1 2018-11-01, 18:00
Posted on 2018-11-13 - 15:06
A series of 2-pyrazolyl
quinolones has been designed and synthesized in 5–7 steps to
optimize for both in vitro antimalarial potency and
various in vitro drug metabolism and pharmacokinetics
(DMPK) features. The most potent compounds display no cross-resistance
with multidrug resistant parasite strains (W2) compared to drug sensitive
strains (3D7), with IC50 (concentration of drug required
to achieve half maximal growth suppression) values in the range of
15–33 nM. Furthermore, members of the series retain moderate
activity against the atovaquone-resistant parasite isolate (TM90C2B).
The described 2-pyrazoyl series displays improved DMPK properties,
including improved aqueous solubility compared to previously reported
quinolone series and acceptable safety margin through in vitro cytotoxicity assessment. The 2-pyrazolyl quinolones are believed
to bind to the ubiquinone-reducing Qi site of the parasite bc1 complex, which is supported by crystallographic
studies of bovine cytochrome bc1 complex.
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Hong, W. David; Leung, Suet C.; Amporndanai, Kangsa; Davies, Jill; Priestley, Richard S.; Nixon, Gemma L.; et al. (2018). Potent Antimalarial 2‑Pyrazolyl Quinolone bc1 (Qi) Inhibitors with Improved
Drug-like Properties. ACS Publications. Collection. https://doi.org/10.1021/acsmedchemlett.8b00371
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AUTHORS (12)
WH
W. David Hong
SL
Suet C. Leung
KA
Kangsa Amporndanai
JD
Jill Davies
RP
Richard S. Priestley
GN
Gemma L. Nixon
NB
Neil G. Berry
SH
S. Samar Hasnain
SA
Svetlana Antonyuk
SW
Stephen A. Ward
GB
Giancarlo A. Biagini
PO
Paul M. O’Neill
KEYWORDS
ubiquinone-reducing Q i sitecytotoxicity assessment2- pyrazolyl quinolonesdrug metabolismDrug-like Propertiesparasite bc 12- pyrazoyl series displaysparasite strainsDMPK propertiesatovaquone-resistant parasitegrowth suppressionQ iquinolone seriesIC 50safety marginTM 90Ccompounds displayantimalarial potencycytochrome bc 1