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

作者：Figueiras Marta; Coelho Lis; Wicht Kathryn J; Santos Sofia A; Lavrado Joao; Gut Jiri; Rosenthal Philip J; Nogueira Fatima; Egan Timothy J; Moreira Rui; Paulo Alexandra^*

来源：Bioorganic & Medicinal Chemistry, 2015, 23(7): 1530-1539.

DOI：10.1016/j.bmc.2015.02.007

• Indolo[3,2-b]quinolines
• Hemozoin
• Malaria
• Vacuolar accumulation
• Resistance

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 (IC(50)s between 20 and 158 nM), good correlation with beta-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.

• 出版日期2015-4-1
• 单位河北医科大学