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-dihydroimidazo­[2,1-<i>b</i>]­[1,3]­oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo­[2,1-<i>b</i>]­[1,3]­oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo­[2,1-<i>b</i>]­[1,3]­oxazepines), 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 (MIC₉₀), 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 (MIC₉₀) 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 IC₅₀ 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

ICC values for clinical questionnaires.

<p>ICC values for clinical questionnaires.</p

Scatterplot of baseline vs. repeat visit FEV₁.

<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 FEV₁. (r = 0.983, p<0.0001; n = 98). <b>B)</b> Bland-Altman plot of baseline mean post-bronchodilator FEV₁ 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

Change from baseline visit.

<p>Change from baseline visit.</p

Demographics, PFTs and six-minute walk.

<p>Demographics, PFTs and six-minute walk.</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