2 research outputs found
Aminopyrazinamides: Novel and Specific GyrB Inhibitors that Kill Replicating and Nonreplicating <i>Mycobacterium tuberculosis</i>
Aminopyrazinamides originated from a high throughput
screen targeting
the <i>Mycobacterium smegmatis</i> (Msm) GyrB ATPase. This
series displays chemical tractability, robust structure–activity
relationship, and potent antitubercular activity. The crystal structure
of Msm GyrB in complex with one of the aminopyrazinamides revealed
promising attributes of specificity against other broad spectrum pathogens
and selectivity against eukaryotic kinases due to novel interactions
at hydrophobic pocket, unlike other known GyrB inhibitors. The aminopyrazinamides
display excellent mycobacterial kill under <i>in vitro</i>, intracellular, and hypoxic conditions
Novel N‑Linked Aminopiperidine-Based Gyrase Inhibitors with Improved hERG and in Vivo Efficacy against Mycobacterium tuberculosis
DNA
gyrase is a clinically validated target for developing drugs
against Mycobacterium tuberculosis (Mtb).
Despite the promise of fluoroquinolones (FQs) as anti-tuberculosis
drugs, the prevalence of pre-existing resistance to FQs is likely
to restrict their clinical value. We describe a novel class of N-linked
aminopiperidinyl alkyl quinolones and naphthyridones that kills Mtb
by inhibiting the DNA gyrase activity. The mechanism of inhibition
of DNA gyrase was distinct from the fluoroquinolones, as shown by
their ability to inhibit the growth of fluoroquinolone-resistant Mtb.
Biochemical studies demonstrated this class to exert its action via
single-strand cleavage rather than double-strand cleavage, as seen
with fluoroquinolones. The compounds are highly bactericidal against
extracellular as well as intracellular Mtb. Lead optimization resulted
in the identification of potent compounds with improved oral bioavailability
and reduced cardiac ion channel liability. Compounds from this series
are efficacious in various murine models of tuberculosis