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

Eur J Med Chem. 2016 Nov 10:123:684-703. doi: 10.1016/j.ejmech.2016.07.068.

Jun-Jie Koh ¹, Hanxun Zou ², Devika Mukherjee ³, Shuimu Lin ², Fanghui Lim ², Javey Khiapeng Tan ², Dhi-Zen Tan ², Bridget L Stocker ⁴, Mattie S M Timmer ⁵, Hilary M Corkran ⁶, Rajamani Lakshminarayanan ⁷, Donald T H Tan ⁸, Derong Cao ⁹, Roger W Beuerman ¹⁰, Thomas Dick ¹¹, Shouping Liu ¹²

Affiliations

1 Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, 119074, Singapore.
2 Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore.
3 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 117545, Singapore.
4 Malaghan Institute of Medical Research, PO Box 7060, Wellington, New Zealand.
5 Victoria University of Wellington, School of Chemical and Physical Science, PO Box 600, Wellington, New Zealand.
6 Malaghan Institute of Medical Research, PO Box 7060, Wellington, New Zealand; Victoria University of Wellington, School of Chemical and Physical Science, PO Box 600, Wellington, New Zealand.
7 Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore; Duke-NUS Medical School, SRP Neuroscience and Behavioural Disorders, 169857, Singapore.
8 Singapore National Eye Centre, 11 Third Hospital Avenue, 168751, Singapore.
9 School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641, China.
10 Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore; Duke-NUS Medical School, SRP Neuroscience and Behavioural Disorders, 169857, Singapore. Electronic address: rwbeuerman@gmail.com.
11 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 117545, Singapore. Electronic address: thomas_dick@nuhs.edu.sg.
12 Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore; Duke-NUS Medical School, SRP Neuroscience and Behavioural Disorders, 169857, Singapore. Electronic address: liushouping@gmail.com.

PMID: 27517813 DOI: 10.1016/j.ejmech.2016.07.068

Abstract

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.

Keywords

Membrane targeting; Mycobacteria; Tuberculosis; Xanthone.

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