N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: design, synthesis and antiplasmodial activity

Marta Figueiras; Lis Coelho; Kathryn J Wicht; Sofia A Santos; João Lavrado; Jiri Gut; Philip J Rosenthal; Fátima Nogueira; Timothy J Egan; Rui Moreira; Alexandra Paulo

doi:10.1016/j.bmc.2015.02.007

N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: design, synthesis and antiplasmodial activity

Bioorg Med Chem. 2015 Apr 1;23(7):1530-9. doi: 10.1016/j.bmc.2015.02.007. Epub 2015 Feb 13.

Authors

Affiliations

¹ Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
² UEI Malaria, Centro da Malária e Doenças Tropicais, IHMT, Universidade Nova de Lisboa, Rua da Junqueira, 100, P-1349-008 Lisboa, Portugal.
³ Department of Chemistry, University of Cape Town, Private Bag X3, Rondebosch 7701, South Africa.
⁴ 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.
⁵ Department of Medicine, San Francisco General Hospital, University of California, San Francisco, Box 0811, San Francisco, CA 94143, USA.
⁶ 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.

PMID: 25725608
DOI: 10.1016/j.bmc.2015.02.007

Abstract

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.

Keywords: Hemozoin; Indolo[3,2-b]quinolines; Malaria; Resistance; Vacuolar accumulation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimalarials / chemical synthesis*
Antimalarials / pharmacology
Cryptolepis
Drug Design*
Hemeproteins / antagonists & inhibitors*
Hemeproteins / metabolism
Humans
Plasmodium falciparum / drug effects*
Quinolines / chemical synthesis*
Quinolines / pharmacology

Substances

Antimalarials
Hemeproteins
Quinolines
hemozoin