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.
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.
ELT Boston, Platform Technology & Science, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.
Lourdes
L
Encinas
Heather
H
O'Keefe
Margarete
M
Neu
Modesto J
MJ
Remuiñán
Amish M
AM
Patel
Ana
A
Guardia
Christopher P
CP
Davie
Natalia
N
Pérez-Macías
Hongfang
H
Yang
Maire A
MA
Convery
Jeff A
JA
Messer
Esther
E
Pérez-Herrán
Paolo A
PA
Centrella
Daniel
D
Alvarez-Gómez
Matthew A
MA
Clark
Sophie
S
Huss
Gary K
GK
O'Donovan
Fátima
F
Ortega-Muro
William
W
McDowell
Pablo
P
Castañeda
Christopher C
CC
Arico-Muendel
Stane
S
Pajk
Joaquín
J
Rullás
Iñigo
I
Angulo-Barturen
Emilio
E
Alvarez-Ruíz
Alfonso
A
Mendoza-Losana
Lluís
L
Ballell Pages
Julia
J
Castro-Pichel
Ghotas
G
Evindar
D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium