- N-Hydroxyformamide LpxC inhibitors, their in vivo efficacy in a mouse Escherichia coli infection model, and their safety in a rat hemodynamic assay
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UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase (LpxC), the zinc metalloenzyme catalyzing the first committed step of lipid A biosynthesis in Gram-negative bacteria, has been a target for antibacterial drug discovery for many years. All inhibitor chemotypes reaching an advanced preclinical stage and clinical phase 1 have contained terminal hydroxamic acid, and none have been successfully advanced due, in part, to safety concerns, including hemodynamic effects. We hypothesized that the safety of LpxC inhibitors could be improved by replacing the terminal hydroxamic acid with a different zinc-binding group. After choosing an N-hydroxyformamide zinc-binding group, we investigated the structure-activity relationship of each part of the inhibitor scaffold with respect to Pseudomonas aeruginosa and Escherichia coli LpxC binding affinity, in vitro antibacterial potency and pharmacological properties. We identified a novel, potency-enhancing hydrophobic binding interaction for an LpxC inhibitor. We demonstrated in vivo efficacy of one compound in a neutropenic mouse E. coli infection model. Another compound was tested in a rat hemodynamic assay and was found to have a hypotensive effect. This result demonstrated that replacing the terminal hydroxamic acid with a different zinc-binding group was insufficient to avoid this previously recognized safety issue with LpxC inhibitors.
- Furuya, Takeru,Shapiro, Adam B.,Comita-Prevoir, Janelle,Kuenstner, Eric J.,Zhang, Jing,Ribe, Seth D.,Chen, April,Hines, Daniel,Moussa, Samir H.,Carter, Nicole M.,Sylvester, Mark A.,Romero, Jan A.C.,Vega, Camilo V.,Sacco, Michael D.,Chen, Yu,O'Donnell, John P.,Durand-Reville, Thomas F.,Miller, Alita A.,Tommasi, Ruben A.
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- Design and synthesis of fluorescent 7-deazaadenosine nucleosides containing π-extended diarylacetylene motifs
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C-modified 7-deazaadenosines containing a diphenylacetylene moiety have been synthesised using cross-coupling approaches. The C-modified nucleosides exhibit remarkable fluorescence properties, including high quantum yields. Solvatochromic studies show a n
- De Ornellas, Sara,Slattery, John M.,Edkins, Robert M.,Beeby, Andrew,Baumann, Christoph G.,Fairlamb, Ian J. S.
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- Effect of extended conjugation with a phenylethynyl group on the fluorescence properties of water-soluble arylboronic acids
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Boronic acids that change fluorescence properties upon sugar binding are very important reporter units for the development of small molecule lectin mimics (boronolectins). Aimed at developing long wavelength fluorescent boronic acid reporter compounds, we
- Zheng, Shi-Long,Lin, Na,Reid, Suazette,Wang, Binghe
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p. 5427 - 5436
(2008/01/07)
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- Microwave-assisted synthesis of ethynylarylboronates for the construction of boronic acid-based fluorescent sensors for carbohydrates
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A reliable and operationally simple procedure for the synthesis of 2,2-dimethylpropane-1,3-diyl ethynylaryl boronates 4 was developed. The key step is microwave-facilitated selective formation of 2,2-dimethylpropane-1,3-diyl trimethylsilylethynylaryl boro
- Zheng, Shi-Long,Reid, Suazette,Lin, Na,Wang, Binghe
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p. 2331 - 2335
(2007/10/03)
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