12 research outputs found
Short and Efficient Synthesis of Oxazinone- and Thiazinone-Containing Bicyclic Heteroaromatic Aldehydes
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>
Pyrazolopyrimidines Establish MurC as a Vulnerable Target in <i>Pseudomonas aeruginosa</i> and <i>Escherichia coli</i>
The bacterial peptidoglycan biosynthesis
pathway provides multiple
targets for antibacterials, as proven by the clinical success of β-lactam
and glycopeptide classes of antibiotics. The Mur ligases play an essential
role in the biosynthesis of the peptidoglycan building block, <i>N</i>-acetyl-muramic acid-pentapeptide. MurC, the first of four
Mur ligases, ligates l-alanine to UDP-<i>N</i>-acetylmuramic
acid, initiating the synthesis of pentapeptide precursor. Therefore,
inhibiting the MurC enzyme should result in bacterial cell death.
Herein, we report a novel class of pyrazolopyrimidines with subnanomolar
potency against both <i>Escherichia coli</i> and <i>Pseudomonas aeruginosa</i> MurC enzymes, which demonstrates
a concomitant bactericidal activity against efflux-deficient strains.
Radio-labeled precursor incorporation showed these compounds selectively
inhibited peptidoglycan biosynthesis, and genetic studies confirmed
the target of pyrazolopyrimidines to be MurC. In the presence of permeability
enhancers such as colistin, pyrazolopyrimidines exhibited low micromolar
MIC against the wild-type bacteria, thereby, indicating permeability
and efflux as major challenges for this chemical series. Our studies
provide biochemical and genetic evidence to support the essentiality
of MurC and serve to validate the attractiveness of target for antibacterial
discovery
Optimization of Pyrrolamides as Mycobacterial GyrB ATPase Inhibitors: Structure-Activity Relationship and In Vivo
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-beta-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 similar to 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 (IC50 < 10 nM) along with potent cellular activity (MIC = 60 nM) against Mtb
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
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