Azaaurones as Potent Antimycobacterial Agents Active against MDR- and XDR-TB

被引：27
作者：
Campanico, Andre [1 ]
Carrasco, Marta P. [1 ]
Njoroge, Mathew [2 ]
Seldon, Ronnett [4 ]
Chibale, Kelly [3 ,4 ,5 ]
Perdigao, Joao [1 ]
Portugal, Isabel [1 ]
Warner, Digby F. [5 ,6 ,7 ]
Moreira, Rui [1 ]
Lopes, Francisca [1 ]
机构：
[1] Univ Lisbon, Inst Invest Med iMed ULisboa, Fac Farm, Av Prof Gama Pinto, P-1649003 Lisbon, Portugal
[2] Univ Cape Town, Div Clin Pharmacol, Dept Med, Drug Discovery & Dev Ctr H3D, ZA-7925 Observatory, South Africa
[3] Univ Cape Town, Dept Chem, ZA-7701 Rondebosch, South Africa
[4] Univ Cape Town, Dept Chem, South African Med Res Council, Drug Discovery & Dev Res Unit, ZA-7701 Rondebosch, South Africa
[5] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7701 Rondebosch, South Africa
[6] Univ Cape Town, Dept Pathol, SAMRC NHLS UCT Mol Mycobacteriol Res Unit, ZA-7701 Rondebosch, South Africa
[7] Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, ZA-7701 Rondebosch, South Africa
来源：
CHEMMEDCHEM | 2019年 / 14卷 / 16期
基金：
英国医学研究理事会;
关键词：
azaaurones; drug discovery; multidrug-resistant tuberculosis; Mycobacterium tuberculosis; MYCOBACTERIUM-TUBERCULOSIS; RESISTANT TUBERCULOSIS; DRUG DISCOVERY; AURONE; BEDAQUILINE; CHALLENGES; SCAFFOLD; TARGET; OPPORTUNITIES; INHIBITION;
D O I：
10.1002/cmdc.201900289
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Herein we report the screening of a small library of aurones and their isosteric counterparts, azaaurones and N-acetylazaaurones, against Mycobacterium tuberculosis. Aurones were found to be inactive at 20 mu m, whereas azaaurones and N-acetylazaaurones emerged as the most potent compounds, with nine derivatives displaying MIC99 values ranging from 0.4 to 2.0 mu m. In addition, several N-acetylazaaurones were found to be active against multidrug-resistant (MDR) and extensively drug-resistant (XDR) clinical M. tuberculosis isolates. The antimycobacterial mechanism of action of these compounds remains to be determined; however, a preliminary mechanistic study confirmed that they do not inhibit the mycobacterial cytochrome bc1 complex. Additionally, microsomal metabolic stability and metabolite identification studies revealed that N-acetylazaaurones are deacetylated to their azaaurone counterparts. Overall, these results demonstrate that azaaurones and their N-acetyl counterparts represent a new entry in the toolbox of chemotypes capable of inhibiting M. tuberculosis growth.
引用
收藏
页码：1537 / 1546
页数：10
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