Synthesis of methyl 5-S-alkyl-5-thio-d-arabinofuranosides and evaluation of their antimycobacterial activity

Aditya K. Sanki, Julie Boucau, Parijat Srivastava, Samuel S. Adams, Donald R. Ronning, Steven J. Sucheck

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The emergence of drug resistant tuberculosis necessitates a search for new antimycobacterial compounds. The antigen 85 (ag85) complex is a family of mycolyl transferases involved in the synthesis of trehalose-6,6′-dimycolate and the mycolated hexasaccharide motif found at the terminus of the arabinogalactan in mycobacterium. Enzymes involved in the synthesis of cell wall structures like these are potential targets for the development of new antiinfectives. To potentially inhibit the ag85 complex, methyl 5-S-alkyl-5-thio-arabinofuranoside analogues were designed based on docking studies with ag85C derived from Mycobacterium tuberculosis. The target arabinofuranosides were then synthesized and the antibacterial activity evaluated against Mycobacterium smegmatis ATCC 14468. Two of the compounds, 5-S-octyl-5-thio-α-d-arabinofuranoside (8) and 5-S-octyl-5-thio-β-d-arabinofuranoside (11), showed MICs of 256 and 512 μg/mL, respectively. Attempts to directly evaluate acyltransferase inhibitory activity of the arabinofuranosides against ag85C are also described. In conclusion, a new class of antimycobacterial arabinofuranosides has been discovered.

Original languageEnglish (US)
Pages (from-to)5672-5682
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number10
DOIs
StatePublished - May 15 2008

Keywords

  • Antigen 85
  • Arabinofuranosides
  • Carbohydrate-based antibiotics
  • Carbohydrates
  • Mycobacterium tuberculosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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