Abstract
A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforward aldol condensation reactions of benzofuranones and the appropriately substituted benzaldehydes. Microwave enhanced synthesis using palladium catalyzed protocols was introduced as a powerful strategy for extending the chemical space around the aurone scaffold. Additionally, Mannich-base derivatives, containing a 7-aminomethyl-6-hydroxy substitution pattern at ring A, were also prepared. Screening against the chloroquine resistant Plasmodium falciparum W2 strain identified novel aurones with IC 50 values in the low micromolar range. The most potent compounds contained a basic moiety, with the ability to accumulate in acidic digestive vacuole of the malaria parasite. However, none of those aurones revealed significant activity against hemozoin formation and falcipain-2, two validated targets expressed during the blood stage of P. falciparum infection and functional in digestive vacuole of the parasite. Overall, this study highlight (i) the usefulness of aurones as platforms for synthetic procedures using palladium catalyzed protocols to rapidly deliver lead compounds for further optimization and (ii) the potential of novel aurone derivatives as promising antimalarial compounds.
Original language | English |
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Pages (from-to) | 523-534 |
Number of pages | 12 |
Journal | European Journal of Medicinal Chemistry |
Volume | 80 |
DOIs | |
Publication status | Published - 10 Jun 2014 |
Externally published | Yes |
Funding
This work was supported by Fundação para a Ciência e Tecnologia (FCT, Portugal) through projects PTDC/SAU-FAR/118459/2010 and Pest-OE/SAL/UI4013/2011. A.S.N. and M.P.C. acknowledge FCT for grants SFRH/BD/41276/2007 and SFRH/BD/61611/2009 , respectively. P.J.R. is a Doris Duke Charitable Foundation Distinguished Clinical Scientist.
Funders | Funder number |
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European Union’s Horizon 2020 - Research and innovation program | 692022, 667824 |
FCT - Fundação para a Ciência e a Tecnologia | PTDC/SAU-FAR/118459/2010, Pest-OE/SAL/UI4013/2011, SFRH/BD/61611/2009 |
Not added | SFRH/BD/41276/2007 |
Keywords
- Aurones
- Cross-coupling reactions
- Malaria
- Plasmodium falciparum