Structure–activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues

• Published in: Bioorganic & medicinal chemistry Vol. 17; no. 20; pp. 7209 - 7217
• Main Authors: Van Baelen, Gitte, Hostyn, Steven, Dhooghe, Liene, Tapolcsányi, Pál, Mátyus, Péter, Lemière, Guy, Dommisse, Roger, Kaiser, Marcel, Brun, Reto, Cos, Paul, Maes, Louis, Hajós, György, Riedl, Zsuzsanna, Nagy, Ildikó, Maes, Bert U.W., Pieters, Luc
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.10.2009; Elsevier
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarial; Antimalarials - pharmacology; Antineoplastic Agents - pharmacology; Antiparasitic; Antiparasitic agents; Antiplasmodial; Azaindole; Biological and medical sciences; Carboline; Cytotoxic; Indole Alkaloids - chemistry; Indole Alkaloids - pharmacology; Indoloisoquinoline; Indoloquinoline alkaloid; Medical sciences; Mice; Pharmacology. Drug treatments; Plasmodium berghei; Plasmodium berghei - drug effects; Plasmodium falciparum; Plasmodium falciparum - drug effects; Pyrroloisoquinoline; Pyrroloquinoline; Structure-Activity Relationship; Indoloquinoline alkaloid; Antiplasmodial; Antimalarial; Pyrroloquinoline; Azaindole; Antiparasitic; Cytotoxic; Carboline; Indoloisoquinoline; Pyrroloisoquinoline; Rat; Nitrogen heterocycle; Toxicity; Cytotoxicity; Antiprotozoal agent; Plasmodium falciparum; Alkaloid; Structure activity relation; Bicyclic compound; Aromatic compound; Chemical synthesis; Protozoa; Apicomplexa; Rodentia; Tricyclic compound; Striated muscle; In vitro; Vertebrata; Mammalia; Carboline derivatives; Cell line; Parasiticide
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.08.057

In a series of carbolines, azaindoles and pyrrolo(iso)quinolines, 2-methyl-β-carboline (9) showed the highest in vitro activity (IC 50 = 0.45 μM) against Plasmodium falciparum K1, without apparent cytotoxicity against L6 cells (SI > 1000). Based on the indoloquinoline alkaloids cryptolepine ( 1), neocryptolepine ( 2), isocryptolepine ( 3) and isoneocryptolepine ( 4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. None of the bicyclic compounds was significantly active against the chloroquine-resistant strain Plasmodium falciparum K1, in contrast to the tricyclic derivatives. The tricyclic compound 2-methyl-2 H-pyrido[3,4- b]indole ( 9), or 2-methyl-β-carboline, showed the best in vitro activity, with an IC 50 value of 0.45 μM against P. falciparum K1, without apparent cytotoxicity against L6 cells (SI > 1000). However, this compound was not active in the Plasmodium berghei mouse model. Structure–activity relationships are discussed and compared with related naturally occurring compounds.