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. 2006 Feb 23;49(4):1455-65.
doi: 10.1021/jm0510023.

Hybrid antibacterials. DNA polymerase-topoisomerase inhibitors

Chengxin Zhi  1 , Zheng-Yu Long, Andrzej Manikowski, Jeanne Comstock, Wei-Chu Xu, Neal C Brown, Paul M Tarantino Jr, Karsten A Holm, Edward J Dix, George E Wright, Marjorie H Barnes, Michelle M Butler, Kimberly A Foster, William A LaMarr, Benoit Bachand, Richard Bethell, Caroline Cadilhac, Sylvie Charron, Serge Lamothe, Irina Motorina, Richard Storer
Affiliations

Hybrid antibacterials. DNA polymerase-topoisomerase inhibitors

Chengxin Zhi et al. J Med Chem. .

Abstract

Novel Gram-positive (Gram+) antibacterial compounds consisting of a DNA polymerase IIIC (pol IIIC) inhibitor covalently connected to a topoisomerase/gyrase inhibitor are described. Specifically, 3-substituted 6-(3-ethyl-4-methylanilino)uracils (EMAUs) in which the 3-substituent is a fluoroquinolone moiety (FQ) connected by various linkers were synthesized. The resulting "AU-FQ" hybrid compounds were significantly more potent than the parent EMAU compounds as inhibitors of pol IIIC and were up to 64-fold more potent as antibacterials in vitro against Gram+ bacteria. The hybrids inhibited the FQ targets, topoisomerase IV and gyrase, with potencies similar to norfloxacin but 10-fold lower than newer agents, for example, ciprofloxacin and sparfloxacin. Representative hybrids protected mice from lethal Staphylococcus aureus infection after intravenous dosing, and one compound showed protective effect against several antibiotic-sensitive and -resistant Gram+ infections in mice. The AU-FQ hybrids are a promising new family of antibacterials for treatment of antibiotic-resistant Gram+ infections.

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Figures

Figure 1
Figure 1
Overview of SAR of fluoroquinolone antibacterial drugs. PK, pharmacokinetics.
Figure 2
Figure 2
Mean plasma concentrations of 5 (■) and its glucuronide metabolite (▲) after a 100 mg/kg iv dose of 5 to mice (n = 3).
Scheme 1
Scheme 1
Retrosynthetic analysis of AU-FQ hybrids.
Scheme 2
Scheme 2
Scheme 3
Scheme 3
Scheme 4
Scheme 4
Scheme 5
Scheme 5
See this image and copyright information in PMC

References

    1. Tarantino P, Zhi C, Gambino J, Wright GE, Brown NC. 6-Anilinouracil-based Inhibitors of Bacillus subtilis DNA Polymerase III: Antipolymerase and Antimicrobial Structure-Activity Relationships Based on Substitution at Uracil N3. J Med Chem. 1999;42:2035–2040. - PubMed
    1. Tarantino P, Zhi C, Wright GE, Brown NC. Inhibitors of DNA Polymerase III as Novel Antimicrobial Agents against Gram-positive Eubacteria. Antimicrob Agents Chemother. 1999;43:1982–1987. - PMC - PubMed
    1. Zhi C, Long ZY, Gambino J, Xu WC, Brown NC, Barnes M, Butler M, LaMarr W, Wright GE. Synthesis of Substituted 6-Aminouracils and Their Inhibition of DNA Polymerase IIIC and Gram-positive Bacterial Growth. J Med Chem. 2003;46:2731–2739. - PubMed
    1. Zhi C, Long Z-Y, Manikowski A, Brown NC, Tarantino PM, Jr, Holm KA, Dix E, Wright GE, Foster KA, Butler MM, LaMarr WA, Skow DJ, Lamothe S, Motorina I. Synthesis and Antibacterial Activity of 3-Substituted-6-(3-ethyl-4-methylanilino)uracils. J Med Chem. in press. - PubMed
    1. Kuhl L, Svenstrup N, Ladel C, Otteneder M, Binas A, Schiffer G, Brands M, Lampe T, Ziegelbauer K, Rübsamen-Waigmann H, Haebich D, Ehlert K. Biological Characterization of Novel Inhibitors of the Gram-Positive DNA Polymerase IIIC Enzyme. Antimicrob Agents Chemother. 2005;49:987–995. - PMC - PubMed

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