title: The effect of chain length and unsaturation on Mtb Dxr inhibition and antitubercular killing activity of FR900098 analogs.
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.
authors.affiliation: Department of Chemistry, George Washington University, 725 21st Street NW, Corcoran 107, Washington, DC 20052, United States.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Jackson
authors.affiliation: Department of Chemistry, George Washington University, 725 21st Street NW, Corcoran 107, Washington, DC 20052, United States.
authors.forename: Géraldine
authors.initials: G
authors.lastname: San Jose
authors.affiliation: Department of Chemistry, George Washington University, 725 21st Street NW, Corcoran 107, Washington, DC 20052, United States.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Brothers
authors.affiliation: Department of Chemistry, George Washington University, 725 21st Street NW, Corcoran 107, Washington, DC 20052, United States.
authors.forename: Emma K
authors.initials: EK
authors.lastname: Edelstein
authors.affiliation: Department of Chemistry, George Washington University, 725 21st Street NW, Corcoran 107, Washington, DC 20052, United States.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Sheldon
authors.affiliation: Department of Chemistry and Biochemistry and the National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA 20110, United States.
authors.forename: Amanda
authors.initials: A
authors.lastname: Haymond
authors.affiliation: Department of Chemistry and Biochemistry and the National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA 20110, United States.
authors.forename: Chinchu
authors.initials: C
authors.lastname: Johny
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, United States.
authors.forename: Helena I
authors.initials: HI
authors.lastname: Boshoff
authors.affiliation: Department of Chemistry and Biochemistry and the National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA 20110, United States.
authors.forename: Robin D
authors.initials: RD
authors.lastname: Couch
authors.affiliation: Department of Chemistry, George Washington University, 725 21st Street NW, Corcoran 107, Washington, DC 20052, United States. Electronic address: cdowd@gwu.edu.
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Dowd
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000502:physiology; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D005578:Fosfomycin; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid
keywords: Antibiotic; Dxr; Mycobacterium tuberculosis; Nonmevalonate pathway