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

页码：1537 / 1546

页数：10

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