Thiazolopyridine Ureas as
Novel Antitubercular Agents
Acting through Inhibition of DNA Gyrase B
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Abstract
A pharmacophore-based search led
to the identification of thiazolopyridine
ureas as a novel scaffold with antitubercular activity acting through
inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding
mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration of the side chains
at the thiazolopyridine ring C-5 position to access the ribose/solvent
pocket. Potent compounds with GyrB IC<sub>50</sub> ≤ 1 nM and
Mtb MIC ≤ 0.1 μM were obtained with certain combinations
of side chains at the C-5 position and heterocycles at the C-6 position
of the thiazolopyridine core. Substitutions at C-5 also enabled optimization
of the physicochemical properties. Representative compounds were cocrystallized
with Streptococcus pneumoniae (Spn)
ParE; these confirmed the binding modes predicted by the homology
model. The target link to GyrB was confirmed by genetic mapping of
the mutations conferring resistance to thiazolopyridine ureas. The
compounds are bactericidal in vitro and efficacious in vivo in an
acute murine model of tuberculosis