The effect of chain length and unsaturation on Mtb Dxr inhibition and antitubercular killing activity of FR900098 analogs |
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| Affiliation: | 1. Department of Chemistry, George Washington University, 725 21st Street NW, Corcoran 107, Washington, DC 20052, United States;2. Department of Chemistry and Biochemistry and the National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA 20110, United States;3. Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, United States;1. Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany;2. Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany;3. EMBL Heidelberg, Genome Biology Unit, Meyerhofstrasse 1, D-69117 Heidelberg, Germany;1. Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, MI 49931, United States;2. Department of Chemistry, Youngstown State University, 1 University Plaza, Youngstown, OH 44555, United States |
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| Abstract: | Inhibition of the nonmevalonate pathway (NMP) of isoprene biosynthesis has been examined as a source of new antibiotics with novel mechanisms of action. Dxr is the best studied of the NMP enzymes and several reports have described potent Dxr inhibitors. Many of these compounds are structurally related to natural products fosmidomycin and FR900098, each bearing retrohydroxamate and phosphonate groups. We synthesized a series of compounds with two to five methylene units separating these groups to examine what linker length was optimal and tested for inhibition against Mtb Dxr. We synthesized ethyl and pivaloyl esters of these compounds to increase lipophilicity and improve inhibition of Mtb growth. Our results show that propyl or propenyl linker chains are optimal. Propenyl analog 22 has an IC50 of 1.07 μM against Mtb Dxr. The pivaloyl ester of 22, compound 26, has an MIC of 9.4 μg/mL, representing a significant improvement in antitubercular potency in this class of compounds. |
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| Keywords: | Nonmevalonate pathway Dxr Antibiotic |
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