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Azaaurones as Potent Antimycobacterial Agents Active against MDR- and XDR-TB |
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| Authors: | André Campaniço Dr Marta P Carrasco Dr Mathew Njoroge Ronnett Seldon Prof Kelly Chibale Dr João Perdigão Prof Isabel Portugal Prof Digby F Warner Prof Rui Moreira Prof Francisca Lopes |
| Affiliation: | 1. Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
These authors contributed equally to this work;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 Department of Chemistry, South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch, 7701 South Africa Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701 South Africa;5. Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal;6. Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701 South Africa Department of Pathology, SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, University of Cape Town, Rondebosch, 7701 South Africa Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Rondebosch, 7701 South Africa |
| 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: | azaaurones drug discovery multidrug-resistant tuberculosis Mycobacterium tuberculosis |
