5 research outputs found
Benzimidazoles: Novel Mycobacterial Gyrase Inhibitors from Scaffold Morphing
Type II topoisomerases are well conserved
across the bacterial
species, and inhibition of DNA gyrase by fluoroquinolones has provided
an attractive option for treatment of tuberculosis (TB). However,
the emergence of fluoroquinolone-resistant strains of <i>Mycobacterium
tuberculosis</i> (<i>Mtb</i>) poses a threat for its
sustainability. A scaffold hopping approach using the binding mode
of novel bacterial topoisomerase inhibitors (NBTIs) led to the identification
of a novel class of benzimidazoles as DNA gyrase inhibitors with potent
anti-TB activity. Docking of benzimidazoles to a NBTI bound crystal
structure suggested that this class of compound makes key contacts
in the enzyme active site similar to the reported NBTIs. This observation
was further confirmed through the measurement of DNA gyrase inhibition,
and activity against <i>Mtb</i> strains harboring mutations
that confer resistance to aminopiperidines based NBTIs and <i>Mtb</i> strains resistant to moxifloxacin. Structure–activity
relationship modification at the C-7 position of the left-hand side
ring provided further avenue to improve hERG selectivity for this
chemical series that has been the major challenges for NBTIs
Left-Hand Side Exploration of Novel Bacterial Topoisomerase Inhibitors to Improve Selectivity against hERG Binding
Structure–activity
relationship (SAR) exploration on the
left-hand side (LHS) of a novel class of bacterial topoisomerase inhibitors led to a significant improvement
in the selectivity against hERG cardiac channel binding with concomitant
potent antimycobacterial activity. Bulky polar substituents at the
C-7 position of the naphthyridone ring did not disturb its positioning
between two base pairs of DNA. Further optimization of the polar substituents
on the LHS of the naphthyridone ring led to potent antimycobacterial
activity (Mtb MIC = 0.06 μM) against <i>Mycobacterium tuberculosis</i> (Mtb). Additionally, this knowledge provided a robust SAR understanding
to mitigate the hERG risk. This compound class inhibits Mtb DNA gyrase
and retains its antimycobacterial activity against moxifloxacin-resistant
strains of Mtb. Finally, we demonstrate <i>in vivo</i> proof
of concept in an acute mouse model of TB following oral administration
of compound <b>19</b>
2‑Phenylindole and Arylsulphonamide: Novel Scaffolds Bactericidal against <i>Mycobacterium tuberculosis</i>
A cellular activity-based screen
on <i>Mycobacterium tuberculosis</i> (Mtb) H37Rv using a
focused library from the AstraZeneca corporate
collection led to the identification of 2-phenylindoles and arylsulphonamides,
novel antimycobacterial scaffolds. Both the series were bactericidal <i>in vitro</i> and in an intracellular macrophage infection model,
active against drug sensitive and drug resistant Mtb clinical isolates,
and specific to mycobacteria. The scaffolds showed promising structure–activity
relationships; compounds with submicromolar cellular potency were
identified during the hit to lead exploration. Furthermore, compounds
from both scaffolds were tested for inhibition of known target enzymes
or pathways of antimycobacterial drugs including InhA, RNA polymerase,
DprE1, topoisomerases, protein synthesis, and oxidative-phosphorylation.
Compounds did not inhibit any of the targets suggesting the potential
of a possible novel mode of action(s). Hence, both scaffolds provide
the opportunity to be developed further as leads and tool compounds
to uncover novel mechanisms for tuberculosis drug discovery
Methyl-Thiazoles: A Novel Mode of Inhibition with the Potential to Develop Novel Inhibitors Targeting InhA in Mycobacterium tuberculosis
InhA
is a well validated Mycobacterium tuberculosis (Mtb) target as evidenced by the clinical success of isoniazid.
Translating enzyme inhibition to bacterial cidality by targeting the
fatty acid substrate site of InhA remains a daunting challenge. The
recent disclosure of a methyl-thiazole series demonstrates that bacterial
cidality can be achieved with potent enzyme inhibition and appropriate
physicochemical properties. In this study, we report the molecular
mode of action of a lead methyl-thiazole, along with analogues with
improved CYP inhibition profile. We have identified a novel mechanism
of InhA inhibition characterized by a hitherto unreported “Y158-out”
inhibitor-bound conformation of the protein that accommodates a neutrally
charged “warhead”. An additional novel hydrophilic interaction
with protein residue M98 allows the incorporation of favorable physicochemical
properties for cellular activity. Notably, the methyl-thiazole prefers
the NADH-bound form of the enzyme with a <i>K</i><sub>d</sub> of ∼13.7 nM, as against the NAD<sup>+</sup>-bound form of
the enzyme
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