TY - JOUR
T1 - N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors
T2 - Design, synthesis and antiplasmodial activity
AU - Figueiras, Marta
AU - Coelho, Lis
AU - Wicht, Kathryn J.
AU - Santos, Sofia A.
AU - Lavrado, João
AU - Gut, Jiri
AU - Rosenthal, Philip J.
AU - Nogueira, Fátima
AU - Egan, Timothy J.
AU - Moreira, Rui
AU - Paulo, Alexandra
N1 - PMID: 25725608
WOS:000350995500019
PY - 2015/4/1
Y1 - 2015/4/1
N2 - 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 158 nM), 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.
AB - 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 158 nM), 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.
KW - Hemozoin
KW - Indolo[3 2-b]quinolines
KW - Malaria
KW - Resistance
KW - Vacuolar accumulation
UR - http://www.scopus.com/inward/record.url?scp=84925522084&partnerID=8YFLogxK
UR - https://novaresearch.unl.pt/en/publications/5c142e9b-82fc-4c67-952c-c5d96610ca94
U2 - 10.1016/j.bmc.2015.02.007
DO - 10.1016/j.bmc.2015.02.007
M3 - Article
C2 - 25725608
AN - SCOPUS:84925522084
SN - 0968-0896
VL - 23
SP - 1530
EP - 1539
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
IS - 7
ER -
