TY - JOUR
T1 - Probing the aurone scaffold against Plasmodium falciparum
T2 - Design, synthesis and antimalarial activity
AU - Carrasco, Marta P.
AU - Newton, Ana S.
AU - Gonçalves, Lídia
AU - Góis, Ana
AU - Machado, Marta
AU - Gut, Jiri
AU - Nogueira, Fátima
AU - Hänscheid, Thomas
AU - Guedes, Rita C.
AU - Dos Santos, Daniel J.V.A.
AU - Rosenthal, Philip J.
AU - Moreira, Rui
PY - 2014/6/10
Y1 - 2014/6/10
N2 - 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.
AB - 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.
KW - Aurones
KW - Cross-coupling reactions
KW - Malaria
KW - Plasmodium falciparum
UR - http://www.scopus.com/inward/record.url?scp=84899988228&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2014.04.076
DO - 10.1016/j.ejmech.2014.04.076
M3 - Article
C2 - 24813880
AN - SCOPUS:84899988228
SN - 0223-5234
VL - 80
SP - 523
EP - 534
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -