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PDBsum entry 4cod
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References listed in PDB file
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Key reference
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Title
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Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of mycobacterium tuberculosis inha.
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Authors
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L.Encinas,
H.O'Keefe,
M.Neu,
M.J.Remuiñán,
A.M.Patel,
A.Guardia,
C.P.Davie,
N.Pérez-Macías,
H.Yang,
M.A.Convery,
J.A.Messer,
E.Pérez-Herrán,
P.A.Centrella,
D.Alvarez-Gómez,
M.A.Clark,
S.Huss,
G.K.O'Donovan,
F.Ortega-Muro,
W.Mcdowell,
P.Castañeda,
C.C.Arico-Muendel,
S.Pajk,
J.Rullás,
I.Angulo-Barturen,
E.Alvarez-Ruíz,
A.Mendoza-Losana,
L.Ballell pages,
J.Castro-Pichel,
G.Evindar.
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Ref.
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J Med Chem, 2014,
57,
1276-1288.
[DOI no: ]
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PubMed id
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Abstract
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Tuberculosis (TB) is one of the world's oldest and deadliest diseases, killing a
person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium
tuberculosis, is the target of the frontline antitubercular drug isoniazid
(INH). Compounds that directly target InhA and do not require activation by
mycobacterial catalase peroxidase KatG are promising candidates for treating
infections caused by INH resistant strains. The application of the encoded
library technology (ELT) to the discovery of direct InhA inhibitors yielded
compound 7 endowed with good enzymatic potency but with low antitubercular
potency. This work reports the hit identification, the selected strategy for
potency optimization, the structure-activity relationships of a hundred
analogues synthesized, and the results of the in vivo efficacy studies performed
with the lead compound 65.
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