Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 123, Issue -, Pages 684-703Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.07.068
Keywords
Mycobacteria; Tuberculosis; Xanthone; Membrane targeting
Categories
Funding
- National Medical Research Council
- SingHealth Foundation
- Singapore Ministry of Health's National Medical Research Council under its Translational Clinical Research Flagship Grant [NMRC/TCR/011-NUHS/2014]
- NUS
- Yong Loo Lin School of Medicine
- Singapore Ministry of Health's National Medical Research Council under its Centre grant 'MINE'/Research Core [4 (NMRC/CG/013/2013)]
- Yong Loo Lin School of Medicine BSL3 Core Facility
- [SHF/FG538P/2013]
- [NMRC/CBRG/0080/2015]
- [NMRC/TCR/R1018]
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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. (C) 2016 Elsevier Masson SAS. All rights reserved.
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