Marta P. Carrasco

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.

Malaria, caused by parasites of the genus Plasmodium, leads to over half a million deaths per year, 90% of which are caused by Plasmodium falciparum. P. vivax usually causes milder forms of malaria; however, P. vivax can remain dormant in the livers of infected patients for weeks or years before re-emerging in a new bout of the disease. The only drugs available that target all stages of the parasite can lead to severe side effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency; hence, there is an urgent need to develop new drugs active against blood and liver stages of the parasite. Different groups have demonstrated that triclosan, a common antibacterial agent, targets the Plasmodium liver enzyme enoyl reductase. Here, we provide 4 independent lines of evidence demonstrating that triclosan specifically targets both wild-type and pyrimethamine-resistant P. falciparum and P. vivax dihydrofolate reductases, classic targets for the blood stage of the parasite. This makes triclosan an exciting candidate for further development as a dual specificity antimalarial, which could target both liver and blood stages of the parasite.

The potential of azaaurones as dual‐stage antimalarial agents was investigated by assessing the effect of a small library of azaaurones on the inhibition of liver and intraerythrocytic lifecycle stages of the malaria parasite. The whole series was screened against the blood stage of a chloroquine‐resistant Plasmodium falciparum strain and the liver stage of P. berghei, yielding compounds with dual‐stage activity and sub‐micromolar potency against erythrocytic parasites. Studies with genetically modified parasites, using a phenotypic assay based on the P. falciparum Dd2‐ScDHODH line, which expresses yeast dihydroorotate dehydrogenase (DHODH), showed that one of the azaaurone derivatives has the potential to inhibit the parasite mitochondrial electron‐transport chain. The global urgency in finding new therapies for malaria, especially against the underexplored liver stage, associated with chemical tractability of azaaurones, warrants further development of this chemotype. Overall, these results emphasize the azaaurone chemotype as a promising scaffold for dual‐stage antimalarials.

Aurones were discovered as sub-micromolar HNE inhibitors. The activity is rationalized by a C-shape conformation that allows tight binding to HNE S1 and S2 pockets.