Amphiphilic xanthones as a potent chemical entity of anti-mycobacterial agents with membrane-targeting properties

Jun Jie Koh, Hanxun Zou, Devika Mukherjee, Shuimu Lin, Fanghui Lim, Javey Khiapeng Tan, Dhi Zen Tan, Bridget L. Stocker, Mattie S.M. Timmer, Hilary M. Corkran, Rajamani Lakshminarayanan, Donald T.H. Tan, Derong Cao, Roger W. Beuerman, Thomas Dick, Shouping Liu

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Tuberculosis (TB) remains a deadly disease and infects one-third of the world's population. Given the low success rates encountered in clinical development, there is an urgent need to identify structurally novel antimicrobials for tuberculosis. The present report details the anti-mycobacterial activities, structure-activity relationships (SARs) and mechanism of action of amphiphilic xanthone derivatives. The xanthones exhibited potent MIC, rapid time-kill and no cross-resistance with the current anti-TB drugs. Evidence is presented that these compounds disrupted the inner membrane and led to ATP depletion. Amphiphilic xanthone derivatives exhibited superior metabolic stability, low cytotoxicity and low activity against the common cytochrome P450. Compound 5 was selected for an in vivo pharmacokinetic study. Its bioavailability at an oral dose of 2 mg/kg was 15%. The xanthones thuse provide valuable insight for the development of a new class of membrane targeting antimycobacterial agents that may assist in overcoming the limitations of the current TB medications.

Original languageEnglish (US)
Pages (from-to)684-703
Number of pages20
JournalEuropean Journal of Medicinal Chemistry
StatePublished - 2016

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


  • Membrane targeting
  • Mycobacteria
  • Tuberculosis
  • Xanthone

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