11 research outputs found
Evaluation of the metabolism, bioactivation and pharmacokinetics of triaminopyrimidine analogs toward selection of a potential candidate for antimalarial therapy
<p>1. During the course of metabolic profiling of lead Compound <b>1</b>, glutathione (GSH) conjugates were detected in rat bile, suggesting the formation of reactive intermediate precursor(s). This was confirmed by the identification of GSH and <i>N</i>-acetylcysteine (NAC) conjugates in microsomal incubations.</p> <p>2. It was proposed that bioactivation of Compound <b>1</b> occurs via the formation of a di-iminoquinone reactive intermediate through the involvement of the C-2 and C-5 nitrogens of the pyrimidine core.</p> <p>3. To further investigate this hypothesis, structural analogs with modifications at the C-5 nitrogen were studied for metabolic activation in human liver microsomes supplemented with GSH/NAC.</p> <p>4. Compounds <b>1</b> and <b>2</b>, which bear secondary nitrogens at the C-5 of the pyrimidine core, were observed to form significant amounts of GSH/NAC-conjugates <i>in vitro</i>, whereas compounds with tertiary nitrogens at C-5 (Compound <b>3</b> and <b>4</b>) formed no such conjugates.</p> <p>5. These observations provide evidence that electron/hydrogen abstraction is required for the bioactivation of the triaminopyrimidines, potentially via a di-iminoquinone intermediate. The lack of a hydrogen and/or steric hindrance rendered Compound <b>3</b> and <b>4</b> incapable of forming thiol conjugates.</p> <p>6. This finding enabled advancement of compound <b>4</b>, with a desirable potency, safety and PK profile, as a lead candidate for further development in the treatment of malaria.</p
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
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
<i>N</i>‑Aryl-2-aminobenzimidazoles: Novel, Efficacious, Antimalarial Lead Compounds
From
the phenotypic screening of the AstraZeneca corporate compound
collection, <i>N</i>-aryl-2-aminobenzimidazoles have emerged
as novel hits against the asexual blood stage of <i>Plasmodium
falciparum</i> (<i>Pf</i>). Medicinal chemistry optimization
of the potency against <i>Pf</i> and ADME properties resulted
in the identification of <b>12</b> as a lead molecule. Compound <b>12</b> was efficacious in the <i>P. berghei</i> (<i>Pb</i>) model of malaria. This compound displayed an excellent
pharmacokinetic profile with a long half-life (19 h) in rat blood.
This profile led to an extended survival of animals for over 30 days
following a dose of 50 mg/kg in the <i>Pb</i> malaria model.
Compound <b>12</b> retains its potency against a panel of <i>Pf</i> isolates with known mechanisms of resistance. The fast
killing observed in the <i>in vitro</i> parasite reduction
ratio (PRR) assay coupled with the extended survival highlights the
promise of this novel chemical class for the treatment of malaria
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
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
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
Aminoazabenzimidazoles, a Novel Class of Orally Active Antimalarial Agents
Whole-cell high-throughput
screening of the AstraZeneca compound
library against the asexual blood stage of Plasmodium
falciparum (<i>Pf</i>) led to the identification
of amino imidazoles, a robust starting point for initiating a hit-to-lead
medicinal chemistry effort. Structure–activity relationship
studies followed by pharmacokinetics optimization resulted in the
identification of <b>23</b> as an attractive lead with good
oral bioavailability. Compound <b>23</b> was found to be efficacious
(ED<sub>90</sub> of 28.6 mg·kg<sup>–1</sup>) in the humanized P. falciparum mouse model of malaria (<i>Pf</i>/SCID model). Representative compounds displayed a moderate to fast
killing profile that is comparable to that of chloroquine. This series
demonstrates no cross-resistance against a panel of <i>Pf</i> strains with mutations to known antimalarial drugs, thereby suggesting
a novel mechanism of action for this chemical class
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
Discovery of Imidazo[1,2‑<i>a</i>]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis
The approval of bedaquiline
to treat tuberculosis has validated
adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report
the discovery of two diverse lead series imidazo[1,2-<i>a</i>]pyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial
ATP synthesis. Through medicinal chemistry exploration, we established
a robust structure–activity relationship of these two scaffolds,
resulting in nanomolar potencies in an ATP synthesis inhibition assay.
A biochemical deconvolution cascade suggested cytochrome c oxidase
as the potential target of IPE class of molecules, whereas characterization
of spontaneous resistant mutants of SQAs unambiguously identified
ATP synthase as its molecular target. Absence of cross resistance
against bedaquiline resistant mutants suggested a different binding
site for SQAs on ATP synthase. Furthermore, SQAs were found to be
noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis
infection