N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: design, synthesis and antiplasmodial activity.
We recently reported that potent N10,O11-bis-alkylamine indolo[3,2-b]quinoline antimalarials act as hemozoin (Hz) growth inhibitors. To improve access and binding to the target we have now designed novel N10,N11-di-alkylamine bioisosteres. 3-Chloro derivatives (10a-f) showed selectivity for malaria parasite compared to human cells, high activity against Plasmodium falciparum chloroquine (CQ)-resistant strain W2 (IC50s between 20 and 158nM), good correlation with β-hematin inhibition and improved vacuolar accumulation ratios, thus suggesting inhibition of Hz growth as one possible mechanism of action for these compounds. Moreover, our studies show that Hz is a valid target for the development of new antimalarials able to overcome CQ resistance.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Marta
M
Figueiras
UEI Malaria, Centro da Malária e Doenças Tropicais, IHMT, Universidade Nova de Lisboa, Rua da Junqueira, 100, P-1349-008 Lisboa, Portugal.
Lis
L
Coelho
Department of Chemistry, University of Cape Town, Private Bag X3, Rondebosch 7701, South Africa.
Kathryn J
KJ
Wicht
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Sofia A
SA
Santos
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
João
J
Lavrado
Department of Medicine, San Francisco General Hospital, University of California, San Francisco, Box 0811, San Francisco, CA 94143, USA.
Jiri
J
Gut
Department of Medicine, San Francisco General Hospital, University of California, San Francisco, Box 0811, San Francisco, CA 94143, USA.
Philip J
PJ
Rosenthal
UEI Malaria, Centro da Malária e Doenças Tropicais, IHMT, Universidade Nova de Lisboa, Rua da Junqueira, 100, P-1349-008 Lisboa, Portugal.
Fátima
F
Nogueira
Department of Chemistry, University of Cape Town, Private Bag X3, Rondebosch 7701, South Africa.
Timothy J
TJ
Egan
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Rui
R
Moreira
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. Electronic address: mapaulo@ff.ulisboa.pt.
Alexandra
A
Paulo
D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D031106:Cryptolepis; D015195:Drug Design; D006420:Hemeproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology
D000962:Antimalarials; D006420:Hemeproteins; D011804:Quinolines; C020753:hemozoin
Hemozoin; Indolo[3,2-b]quinolines; Malaria; Resistance; Vacuolar accumulation