- Discovery of novel bacterial RNA polymerase inhibitors: Pharmacophore-based virtual screening and hit optimization
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The bacterial RNA polymerase (RNAP) is a validated target for broad spectrum antibiotics. However, the efficiency of drugs is reduced by resistance. To discover novel RNAP inhibitors, a pharmacophore based on the alignment of described inhibitors was used for virtual screening. In an optimization process of hit compounds, novel derivatives with improved in vitro potency were discovered. Investigations concerning the molecular mechanism of RNAP inhibition reveal that they prevent the protein-protein interaction (PPI) between σ70 and the RNAP core enzyme. Besides of reducing RNA formation, the inhibitors were shown to interfere with bacterial lipid biosynthesis. The compounds were active against Gram-positive pathogens and revealed significantly lower resistance frequencies compared to clinically used rifampicin.
- Hinsberger, Stefan,Hüsecken, Kristina,Groh, Matthias,Negri, Matthias,Haupenthal, J?rg,Hartmann, Rolf W.
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p. 8332 - 8338
(2013/12/04)
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- Discovery and initial development of a novel class of antibacterials: Inhibitors of Staphylococcus aureus transcription/translation
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The novel bacterial transcription/translation (TT) inhibitor 1 was identified through a combination of high throughput screening and exploratory medicinal chemistry. Initial optimization of the anthranilic acid moiety and sulfonamide amine diversity was accomplished via 1- and two-dimensional solution phase libraries, resulting in an improvement in the MIC of the lead from 64 to 8 μg/mL (compound 4l). Subsequent modification of the central aromatic ring and further refinement of the sulfonamide amines required the development of a solid phase route on Wang resin. The resulting libraries generated a number of potent antibacterials with MICs of ≤1 μg/mL (e.g., 10b, 12, and 13). During the course of this work, it became apparent that the antibacterial activity of the series is not fully correlated with TT inhibition, suggesting that at least one additional mechanism of action is operative.
- Larsen, Scott D.,Hester, Matthew R.,Craig Ruble,Kamilar, Gregg M.,Romero, Donna L.,Wakefield, Brian,Melchior, Earline P.,Sweeney, Michael T.,Marotti, Keith R.
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p. 6173 - 6177
(2007/10/03)
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- Probenecidoxymethyl and 1-ethyl esters of ampicillin
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New ampicillin derivatives, probenecidoxymethyl and 1-ethyl esters of ampicillin and their pharmaceutically acceptable salts, useful as antibiotics. A method for preparing these antibiotics by condensing probenecidoxymethyl or 1-ethyl halide with an acid
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