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PDBsum entry 6haw
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Electron transport
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PDB id
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6haw
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Contents |
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438 a.a.
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413 a.a.
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378 a.a.
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239 a.a.
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196 a.a.
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99 a.a.
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74 a.a.
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64 a.a.
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46 a.a.
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59 a.a.
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References listed in PDB file
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Key reference
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Title
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Potent antimalarial 2-Pyrazolyl quinolone bc1 (qi) inhibitors with improved drug-Like properties.
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Authors
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W.David hong,
S.C.Leung,
K.Amporndanai,
J.Davies,
R.S.Priestley,
G.L.Nixon,
N.G.Berry,
S.Samar hasnain,
S.Antonyuk,
S.A.Ward,
G.A.Biagini,
P.M.O'Neill.
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Ref.
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ACS Med Chem Lett, 2018,
9,
1205-1210.
[DOI no: ]
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PubMed id
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Abstract
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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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