Please use this identifier to cite or link to this item: https://doi.org/10.1021/acs.jmedchem.6b01530
Title: Amphiphilic Indole Derivatives as Antimycobacterial Agents: Structure-Activity Relationships and Membrane Targeting Properties
Authors: Yang, Tianming 
Moreira, Wilfried 
Nyantakyi, Samuel Agyei
Chen, Huan
Aziz, Dinah Binte 
Go, Mei-Lin 
Dick, Thomas 
Keywords: Science & Technology
Life Sciences & Biomedicine
Chemistry, Medicinal
Pharmacology & Pharmacy
MYCOBACTERIUM-TUBERCULOSIS
CARBOXYL METHYLTRANSFERASE
BACTERIAL-MEMBRANES
INFECTIOUS-DISEASES
DRUG DISCOVERY
INHIBITION
TRANSITION
RESISTANCE
MECHANISM
POTENT
Issue Date: 13-Apr-2017
Publisher: AMER CHEMICAL SOC
Citation: Yang, Tianming, Moreira, Wilfried, Nyantakyi, Samuel Agyei, Chen, Huan, Aziz, Dinah Binte, Go, Mei-Lin, Dick, Thomas (2017-04-13). Amphiphilic Indole Derivatives as Antimycobacterial Agents: Structure-Activity Relationships and Membrane Targeting Properties. JOURNAL OF MEDICINAL CHEMISTRY 60 (7) : 2745-2763. ScholarBank@NUS Repository. https://doi.org/10.1021/acs.jmedchem.6b01530
Abstract: Antibacterials that disrupt cell membrane function have the potential to eradicate “persister” organisms and delay the emergence of resistance. Here we report the antimycobacterial activities of 4-fluoro and 6-methoxyindoles bearing a cationic amphiphilic motif represented by a lipophilic n-octyl side chain at position 1 and a positively charged azepanyl or 1,4-dioxa-8-azaspiro[4.5]decane moiety at position 3. These analogues exhibited balanced profiles of potency (Mycobacterium bovis BCG, M tuberculosis H37Rv), selective activity, solubility, and metabolic stability. Bacteriological mechanism of action investigations on a representative analogue revealed cell membrane permeabilization and depolarization in M bovis BCG. These membrane-related changes preceded cell death indicating that the loss in membrane integrity was not an epiphenomenon. Bactericidal activity was observed against both growing and nongrowing mycobacterial cultures. The analogue also upregulated cell envelope stress-inducible promoters piniBAC and pclgR, implicating the involvement of envelope-related targets in its mode of action.
Source Title: JOURNAL OF MEDICINAL CHEMISTRY
URI: https://scholarbank.nus.edu.sg/handle/10635/225236
ISSN: 00222623
15204804
DOI: 10.1021/acs.jmedchem.6b01530
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