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

André Campaniço; Marta P Carrasco; Mathew Njoroge; Ronnett Seldon; Kelly Chibale; João Perdigão; Isabel Portugal; Digby F Warner; Rui Moreira; Francisca Lopes

doi:10.1002/cmdc.201900289

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

ChemMedChem. 2019 Aug 20;14(16):1537-1546. doi: 10.1002/cmdc.201900289. Epub 2019 Jul 25.

Authors

André Campaniço¹, Marta P Carrasco¹, Mathew Njoroge², Ronnett Seldon³, Kelly Chibale^{4

3

5}, João Perdigão¹, Isabel Portugal¹, Digby F Warner^{5

6

7}, Rui Moreira¹, Francisca Lopes¹

Affiliations

¹ Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
² Division of Clinical Pharmacology, Department of Medicine, Drug Discovery and Development Centre (H3D), University of Cape Town, Observatory, 7925, South Africa.
³ Department of Chemistry, South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch, 7701, South Africa.
⁴ Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa.
⁵ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701, South Africa.
⁶ Department of Pathology, SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, University of Cape Town, Rondebosch, 7701, South Africa.
⁷ Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Rondebosch, 7701, South Africa.

PMID: 31294529
DOI: 10.1002/cmdc.201900289

Abstract

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 μm, whereas azaaurones and N-acetylazaaurones emerged as the most potent compounds, with nine derivatives displaying MIC₉₉ values ranging from 0.4 to 2.0 μm. 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.

Keywords: Mycobacterium tuberculosis; azaaurones; drug discovery; multidrug-resistant tuberculosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antitubercular Agents / chemical synthesis
Antitubercular Agents / metabolism
Antitubercular Agents / pharmacology*
Benzofurans / chemical synthesis
Benzofurans / metabolism
Benzofurans / pharmacology*
Drug Resistance, Multiple, Bacterial / drug effects*
Drug Stability
HEK293 Cells
Humans
Indoles / chemical synthesis
Indoles / metabolism
Indoles / pharmacology*
Mice
Microbial Sensitivity Tests
Microsomes, Liver / metabolism
Mycobacterium tuberculosis / drug effects*
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / metabolism
Small Molecule Libraries / pharmacology

Substances

Antitubercular Agents
Benzofurans
Indoles
Small Molecule Libraries