Synthesis and antiplasmodial activity in vitro of new ferrocene-chloroquine analogues

The synthesis of the new compounds (7-chloroquinolin-4-yl)- N'-(1'-dimethylaminomethylferrocen-1-ylmethyl)amine (4a) and N-(7-chloroquinolin-4-yl)-N'-(1'-dimethylaminomethylferrocen-1-ylmethyl)-ethane- 1,2-diamine (6a) is reported. The key step in the synthesis is the cleavage of a ferrocene - Sn bond with n-BuLi to give a lithiumferrocenide species ( 10), which is then treated with an electrophile. Thus, 1'-dimethylaminomethyl-1-tri-n-butylstannylferrocene (11) and subsequently 1'-dimethylaminomethylferrocene-1-carbaldehyde (7a) were synthesised from 1,1'-bis(tri-n-butylstannyl) ferrocene, employing [CH2 = NMe2] I and DMF to introduce the amine and then the aldehyde functionalities. In addition, the compound 1'-dimethylaminomethyl-1-lithiumferrocenide was isolated and the H-1 and C-13 NMR data are reported. X-Ray crystal and molecular structures are reported for compound 4a and the related compound N-(7-chloroquinolin-4-yl)- N'-(2-dimethylaminomethylferrocen-1-ylmethyl)- ethane-1,2-diamine (5a). The antiplasmodial activity in vitro against chloroquine sensitive and resistant strains of Plasmodium falciparum is reported and compared to a series of ferrocene, ruthenocene and phenylene analogues.