Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 19, Issue 8, Pages 2696-2706Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2011.02.053
Keywords
Antibiotic; Pantothenamide; Diastereoselective synthesis; Resistance
Funding
- Canadian Institute of Health Research (CIHR)
- National Science and Engineering Research Council of Canada (NSERC)
- CIHR Chemical Biology Training
- Fonds quebecois de la recherche sur la nature et les technologies (FQRNT)
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As a key precursor of coenzyme A (CoA) biosynthesis, pantothenic acid has proven to be a useful backbone to elaborate probes of this biosynthetic pathway, study CoA-utilizing systems, and design molecules with antimicrobial activity. The increasing prevalence of bacterial strains resistant to one or more antibiotics has prompted a renewed interest for molecules with a novel mode of antibacterial action such as N-substituted pantothenamides. Although numerous derivatives have been reported, most are varied at the terminal N-substituent, and fewer at the beta-alanine moiety. Modifications at the pantoyl portion are limited to the addition of an omega-methyl group. We report a synthetic route to N-substituted pantothenamides with various alkyl substituents replacing the geminal dimethyl groups. Our methodology is also applicable to the synthesis of pantothenic acid, pantetheine and CoA derivatives. Here a small library of new N-substituted pantothenamides was synthesized. Most of these compounds display antibacterial activity against sensitive and resistant Staphylococcus aureus. Interestingly, replacement of the ProR methyl with an allyl group yielded a new N-substituted pantothenamide which is amongst the most potent reported so far. (C) 2011 Elsevier Ltd. All rights reserved.
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