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

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.