title: Bis-alkylamine quindolone derivatives as new antimalarial leads.
abstract: 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.
authors.affiliation: iMed.UL, Faculdade de Farmácia, Universidade de Lisboa, Av Prof Gama Pinto 1649-003 Lisboa, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Lavrado
authors.forename: Kaamil
authors.initials: K
authors.lastname: Gani
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Nobre
authors.forename: Sofia A
authors.initials: SA
authors.lastname: Santos
authors.forename: Paula
authors.initials: P
authors.lastname: Figueiredo
authors.forename: Dinora
authors.initials: D
authors.lastname: Lopes
authors.forename: Virgílio do
authors.initials: Vd
authors.lastname: Rosário
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Alexandra
authors.initials: A
authors.lastname: Paulo
mesh_terms: 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
chemical_list: D000962:Antimalarials; D002243:Carbolines; D006420:Hemeproteins; D045563:Indolequinones; D015363:Quinolones; C020753:hemozoin