Probing the Azaaurone Scaffold against the Hepatic and Erythrocytic Stages of Malaria Parasites. (19th August 2016)

• Record Type: Journal Article
• Authors: Carrasco, Marta P.; Machado, Marta; Gonçalves, Lídia; Sharma, Moni; Gut, Jiri; Lukens, Amanda K.; Wirth, Dyann F.; André, Vânia; Duarte, Maria Teresa; Guedes, Rita C.; dos Santos, Daniel J. V. A.; Rosenthal, Philip J.; Mazitschek, Ralph; Prudêncio, Miguel; Moreira, Rui
• Is Part Of: ChemMedChem. Volume 11:Number 19(2016)
• Page Start: 2194
• Page End: 2204
• Publication Date: 2016-08-19
• Subjects: antiprotozoal agents -- azaaurones -- erythrocytic stage -- liver stage -- malaria; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600327
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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‐ Sc DHODH 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. Abstract : Once bitten, twice potent : Novel synthetic azaaurone derivatives were synthesized and screened against the blood stage of a chloroquine‐resistant P. falciparum strain and the liver stage of P. berghei . Our report shows several compounds with dual‐stage activity and nanomolar potency against erythrocytic parasite, indicating that the azaaurone chemotype is a promising scaffold for dual‐stage antimalarial agents.