Synthesis and activity of some antimalarial bisquinolinemethanols

A new type of bisquinoline antimalarial, containing the basic side chain of the cinchona alkaloids, has been evaluated. Five bis ethers, from 10,11-dihydrocupreine linked through the 6'-hydroxy group by -(CH2)(2n)-bridges (n = 2-5) (series A), and six bis amides, from 8'-amino-10,11-dihydrocinchonidine linked by -CO(CH2)(2n)CO- bridges (n = 1-6) (series B), were synthesized and screened against chloroquine-sensitive and -resistant strains and a mefloquine-resistant strain of Plasmodium falciparum in vitro. Two analogues of series B (n = 4, 5), with a 2-(dibutylamino)-1-hydroxyethyl side chain (series C), were also included. Compounds within series A were generally least active. Among the rest were compounds as active as mefloquine, with diminished cross-resistance to the mefloquine-resistant strain. The most potent (series B, n = 4) was highly active against chloroquine-sensitive, chloroquine-resistant and mefloquine-resistant parasites. In vivo testing, however, showed the compound to be too toxic for further development.