Bis-alkylamine quindolone derivatives as new antimalarial leads

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 19; pp. 5634 - 5637
• Main Authors: Lavrado, João, Gani, Kaamil, Nobre, Pedro A., Santos, Sofia A., Figueiredo, Paula, Lopes, Dinora, Rosário, Virgílio do, Gut, Jiri, Rosenthal, Philip J., Moreira, Rui, Paulo, Alexandra
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.10.2010; Elsevier
• Subjects: Alkylation; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - toxicity; Antiparasitic agents; Antiplasmodial; Biological and medical sciences; Carbolines - chemical synthesis; Carbolines - chemistry; Carbolines - toxicity; Digestive vacuole; Drug Resistance; Hemeproteins - chemistry; Hemeproteins - metabolism; Hemozoin; Hep G2 Cells; Humans; Indolequinones - chemical synthesis; Indolequinones - chemistry; Indolequinones - toxicity; Indoloquinoline; Malaria; Medical sciences; Pharmacology. Drug treatments; Plasmodium falciparum - drug effects; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - toxicity; Indoloquinoline; Antiplasmodial; Malaria; Digestive vacuole; Hemozoin; Protozoa; Antimalarial; Apicomplexa; Liver; Cytotoxicity; Phagosome; In vitro; Biological activity; Antiprotozoal agent; Plasmodium falciparum; Cell line; Chlorine Organic compounds; Tertiary amine; Pigments; Parasiticide; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.08.043

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.