Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

Miyamoto Y.; Kalisiak J.; Korthals K.Lauwaet T.Cheung D.Y.Lozano R.Cobo E.R.Upcroft P.Upcroft J.A.Berg D.E.Gillin F.D.Fokin V.V.Sharpless K.B.Eckmann L.

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Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

机译：Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

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Metronidazole and other 5-nitroimidazoles (5-NI) are among the most effective antimicrobials available against many important anaerobic pathogens, but evolving resistance is threatening their long-term clinical utility. The common 5-NIs were developed decades ago, yet little 5-NI drug development has since taken place, leaving the true potential of this important drug class unexplored. Here we report on a unique approach to the modular synthesis of diversified 5-NIs for broad exploration of their antimicrobial potential. Many of the more than 650 synthesized compounds, carrying structurally diverse functional groups, have vastly improved activity against a range of microbes, including the pathogenic protozoa Giardia lamblia and Trichomonas vaginalis, and the bacterial pathogens Helicobacter pylori, Clostridium difficile, and Bacteroides fragilis. Furthermore, they can overcome different forms of drug resistance, and are active and nontoxic in animal infection models. These findings provide impetus to the development of structurally diverse, next-generation 5-NI drugs as agents in the antimicrobial armamentarium, thus ensuring their future viability as primary therapeutic agents against many clinically important infections.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第43期|17564-17569|共6页
作者
Miyamoto Y.; Kalisiak J.; Korthals K.Lauwaet T.Cheung D.Y.Lozano R.Cobo E.R.Upcroft P.Upcroft J.A.Berg D.E.Gillin F.D.Fokin V.V.Sharpless K.B.Eckmann L.;
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作者单位

Departments of Medicine, University of California, San Diego, San Diego, CA 92093, United States;

Department of Chemistry, Skaggs Institute for Chemical Biology, Scripps Research Institute, San Diego, CA 92037, United States;

Departments of Pathology, University of California, San Diego, San Diego, CA 92093, United StatesQueensland Institute of Medical Research, Brisbane, QLD 4006, Australia;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Antibiotics; Infectious diseases; Medicinal chemistry;

Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

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