12 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
Biarylmethoxy Nicotinamides As Novel and Specific Inhibitors of <i>Mycobacterium tuberculosis</i>
A whole cell based screening effort
on a focused library from corporate
collection resulted in the identification of biarylmethoxy nicotinamides
as novel inhibitors of <i>M. tuberculosis</i> (Mtu) H37Rv.
The series exhibited tangible structure–activity relationships,
and during hit to lead exploration, a cellular potency of 100 nM was
achieved, which is an improvement of >200-fold from the starting
point.
The series is very specific to Mtu and noncytotoxic up to 250 μM
as measured in the mammalian cell line THP-1 based cytotoxicity assay.
This compound class retains its potency on several drug sensitive
and single drug resistant clinical isolates, which indicate that the
compounds could be acting through a novel mode of action
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
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
Lead Optimization of 1,4-Azaindoles as Antimycobacterial Agents
In a previous
report, we described the discovery of 1,4-azaindoles, a chemical series
with excellent in vitro and in vivo antimycobacterial potency through
noncovalent inhibition of decaprenylphosphoryl-β-d-ribose-2′-epimerase
(DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase
6 (PDE6) off-target activity limited its advancement. Herein, we report
lead optimization of this series, culminating in potent, metabolically
stable compounds that have a robust pharmacokinetic profile without
any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles
in a rat chronic TB infection model. We believe that compounds from
the 1,4-azaindole series are suitable for in vivo combination and
safety studies
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
Thiazolopyridine Ureas as Novel Antitubercular Agents Acting through Inhibition of DNA Gyrase B
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
Azaindoles: Noncovalent DprE1 Inhibitors from Scaffold Morphing Efforts, Kill Mycobacterium tuberculosis and Are Efficacious <i>in Vivo</i>
We report 1,4-azaindoles as a new
inhibitor class that kills Mycobacterium tuberculosis <i>in vitro</i> and demonstrates efficacy in mouse tuberculosis
models. The series emerged from scaffold morphing efforts and was
demonstrated to noncovalently inhibit decaprenylphosphoryl-β-d-ribose2′-epimerase (DprE1). With “drug-like”
properties and no expectation of pre-existing resistance in the clinic,
this chemical class has the potential to be developed as a therapy
for drug-sensitive and drug-resistant tuberculosis
4‑Aminoquinolone Piperidine Amides: Noncovalent Inhibitors of DprE1 with Long Residence Time and Potent Antimycobacterial Activity
4-Aminoquinolone piperidine amides
(AQs) were identified as a novel
scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the
minimum inhibitory concentrations, followed by whole genome sequencing
of mutants raised against AQs, identified decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1) as the primary target responsible
for the antitubercular activity. Mass spectrometry and enzyme kinetic
studies indicated that AQs are noncovalent, reversible inhibitors
of DprE1 with slow on rates and long residence times of ∼100
min on the enzyme. In general, AQs have excellent leadlike properties
and good in vitro secondary pharmacology profile. Although the scaffold
started off as a single active compound with moderate potency from
the whole cell screen, structure–activity relationship optimization
of the scaffold led to compounds with potent DprE1 inhibition (IC<sub>50</sub> < 10 nM) along with potent cellular activity (MIC = 60
nM) against Mtb