Bis-alkylamine quindolone derivatives as new antimalarial leads.
Quindolone derivatives, designed to target the malaria parasite digestive vacuole and heme detoxification pathway, have been synthesized by reaction with 2-chloro-N,N-diethylethanamine. This reaction gave N,O-, N,N- and O-alkylated products containing one or two basic side-chains. The compounds were evaluated for antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum W2 strain and for cytotoxicity in HepG2 A16 hepatic cells. By incorporating alkylamine side chains and chlorine atoms in the quindolone nucleus we transformed the inactive tetracyclic parent quindolones into moderate or highly active and selective antimalarial compounds. The most active and selective compound, 5c, showed an IC(50)=51 nM for P. falciparum and a selectivity ratio of 98.
Lavrado
João
J
iMed.UL, Faculdade de Farmácia, Universidade de Lisboa, Av Prof Gama Pinto 1649-003 Lisboa, Portugal.
Gani
Kaamil
K
Nobre
Pedro A
PA
Santos
Sofia A
SA
Figueiredo
Paula
P
Lopes
Dinora
D
Rosário
Virgílio do
Vd
Gut
Jiri
J
Rosenthal
Philip J
PJ
Moreira
Rui
R
Paulo
Alexandra
A
D000478:Alkylation; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D004351:Drug Resistance; D006420:Hemeproteins / Q000737:chemistry / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D045563:Indolequinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D010963:Plasmodium falciparum / Q000187:drug effects; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
D000962:Antimalarials; D002243:Carbolines; D006420:Hemeproteins; D045563:Indolequinones; D015363:Quinolones; C020753:hemozoin