Synthesis and antimalarial activity in vitro of new ruthenocene-chloroquine analogues

The syntheses of the new compounds (7-chloroquinolin-4-yl)(2-dimethylaminomethylruthenocen-1-ylmethyl)amine 3 and N-(7-chloroquinolin-4-yl)-N'-(2-dimethylaminomethylruthenocen-1-ylmethyl)ethane-1,2-diamine 5 are reported. The reactions are compared to those previously reported for the preparation of the ferrocene analogues. The key step in the reaction is the regioselective synthesis of 2-dimethylaminomethylruthenocene carboxaldehyde 10 by deprotonation of dimethylaminomethylruthenocene with t-BuLi in diethyl ether, followed by the addition of DME In addition, 1'-dimethylaminomethylruthenocene carboxaldehyde 11 was also prepared leading to the unexpected synthesis of the 1,1'-isomers (7-chloroquinolin-4-yl)(l'-dimethylaminomethylruthenocen-1-ylmethyl)amine 17 and N-(7-chloroquinolin-4-yl)-N'-(1'-dimethylaminomethylruthenocen-1-ylmethyl)ethane-1,2-diamine 18. X-Ray crystal and molecular structures for compounds 3 and 17.H2O are reported. The 4-aminoquinoline complexes show high efficacy against the chloroquine sensitive and resistant strains of the Plasmodium falciparum parasite in vitro; these results are compared with those obtained for the analogous ferrocene compounds.