15 research outputs found
Antitubercular Nitroimidazoles Revisited: Synthesis and Activity of the Authentic 3‑Nitro Isomer of Pretomanid
A published
study of structural features associated with the aerobic
and anaerobic activities of 4- and 5-nitroimidazoles had found that
the 3-nitro isomer of pretomanid, <b>8</b>, displayed interesting
potencies, including against nitroreductase mutant <i>Mycobacterium
tuberculosis</i>. However, recent nuclear magnetic resonance
analyses of two trace byproducts, isolated from early process optimization
studies toward a large-scale synthesis of pretomanid, raised structural
assignment queries, particularly for <b>8</b>, stimulating further
investigation. Following our discovery that the reported compound
was a 6-nitroimidazooxazole derivative, we developed a <i>de
novo</i> synthesis of authentic <b>8</b> via nitration
of the chiral des-nitro imidazooxazine alcohol <b>26</b> in
trifluoroacetic or acetic anhydride, and verified its identity through
an X-ray crystal structure. Unfortunately, <b>8</b> displayed
no antitubercular activity (MICs > 128 μM), whereas the second
byproduct (3′-methyl pretomanid) was eight-fold more potent
than pretomanid in the aerobic assay. These findings further clarify
target specificities for bicyclic nitroimidazoles, which may become
important in the event of any future clinical resistance
World watch list for domestic animal diversity
Discovery
of the potent antileishmanial effects of antitubercular
6-nitro-2,3-dihydroimidazoÂ[2,1-<i>b</i>]Â[1,3]Âoxazoles and
7-substituted 2-nitro-5,6-dihydroimidazoÂ[2,1-<i>b</i>]Â[1,3]Âoxazines
stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazoÂ[2,1-<i>b</i>]Â[1,3]Âoxazepines), but the results for these seemed less
attractive. Following the screening of a 900-compound pretomanid analogue
library, several hits with more suitable potency, solubility, and
microsomal stability were identified, and the superior efficacy of
newly synthesized 6<i>R</i> enantiomers with phenylpyridine-based
side chains was established through head-to-head assessments in a <i>Leishmania donovani</i> mouse model. Two such leads (<i>R</i>-<b>84</b> and <i>R</i>-<b>89</b>) displayed promising activity in the more stringent <i>Leishmania
infantum</i> hamster model but were unexpectedly found to be
potent inhibitors of hERG. An extensive structure–activity
relationship investigation pinpointed two compounds (<i>R</i>-<b>6</b> and pyridine <i>R</i>-<b>136</b>)
with better solubility and pharmacokinetic properties that also provided
excellent oral efficacy in the same hamster model (>97% parasite
clearance
at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional
profiling earmarked <i>R</i>-<b>6</b> as the favored
backup development candidate
6‑Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis
Bedaquiline (<b>1</b>) is a
new drug for tuberculosis and the first of the diarylquinoline class.
It demonstrates excellent efficacy against TB but induces phospholipidosis
at high doses, has a long terminal elimination half-life (due to its
high lipophilicity), and exhibits potent hERG channel inhibition,
resulting in clinical QTc interval prolongation. A number of structural
ring A analogues of bedaquiline have been prepared and evaluated for
their anti-<i>M.tb</i> activity (MIC<sub>90</sub>), with
a view to their possible application as less lipophilic second generation
compounds. It was previously observed that a range of 6-substituted
analogues of <b>1</b> demonstrated a positive correlation between
potency (MIC<sub>90</sub>) toward <i>M.tb</i> and drug lipophilicity.
Contrary to this trend, we discovered, by virtue of a clogP/<i>M.tb</i> score, that a 6-cyano (CN) substituent provides a substantial
reduction in lipophilicity with only modest effects on MIC values,
suggesting this substituent as a useful tool in the search for effective
and safer analogues of <b>1</b>
Identification of Less Lipophilic Riminophenazine Derivatives for the Treatment of Drug-Resistant Tuberculosis
Clofazimine (CFZ), a member of the riminophenazine class,
has been studied in clinical trials for the treatment of multidrug-resistant
tuberculosis (MDR-TB). CFZ has several side effects which can be attributed
to its extremely high lipophilicity. A series of novel riminophenazine
analogues bearing a C-2 pyridyl substituent was designed and synthesized
with the goal of maintaining potent activity against Mycobacterium tuberculosis (M. tuberculosis) while improving upon its safety profile by lowering the lipophilicity.
All compounds were evaluated for their in vitro activity and cytotoxicity.
The results demonstrated that many new compounds had potent activity
against M. tuberculosis with MICs of
less than 0.03 μg/mL and low cytotoxicity with IC<sub>50</sub> values greater than 64 μg/mL. Some compounds were tested for
in vivo efficacy against MDR-TB in an experimental mouse infection
model. Two compounds demonstrated equivalent or better efficacy than
CFZ in this model with significantly reduced skin discoloration potential
Measures dependent of patient recall: Disease diagnosis and exacerbations.
<p>Measures dependent of patient recall: Disease diagnosis and exacerbations.</p
Scatterplot of baseline vs. repeat visit FEV<sub>1</sub>.
<p>Subjects are color coded by GOLD stratification (using PFT values only). GOLD 0 = red, GOLD 1 = green, GOLD 2 = Blue, GOLD 3 = orange and GOLD 4 = Purple. The solid black line is drawn as a line of identity to visualize differences between baseline and the repeat visit. <b>A)</b> Correlation between the baseline and repeat visit FEV<sub>1</sub>. (r = 0.983, p<0.0001; n = 98). <b>B)</b> Bland-Altman plot of baseline mean post-bronchodilator FEV<sub>1</sub> by the difference between visits. The solid red line = the mean difference, the dotted red line is ± 1 SE and the dashed blue line is ± 1 SD.</p
Six minute walk distance.
<p>The subjects are color coded by GOLD classification as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0184606#pone.0184606.g001" target="_blank">Fig 1A</a>) Scatterplot of the six-minute walk distance at the baseline and repeat visits (r = 0.829, p<0.0001; n = 92). The solid black line is drawn as a line of identity to visualize differences between the baseline and the repeat visits. B) Bland-Altman plot of the mean distance for each subject (baseline and repeat) by the difference between visits. The solid red line = the mean difference, the dotted red line is ± 1 SE and the Dashed blue line is ± 1 SD.</p