Synthesis and antiplasmodial activity in vitro of new ferrocene– chloroquine analogues † Paul Beagley, a Margaret A. L. Blackie, a Kelly Chibale,* a Cailean Clarkson, b Reinout Meijboom, a John R. Moss,* a Peter J. Smith b and Hong Su a a Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa. E-mail: jrm@science.uct.ac.za; chibale@science.uct.ac.za b Department of Pharmacology, University of Cape Town Medical School, Observatory 7925, South Africa Received 24th March 2003, Accepted 6th June 2003 First published as an Advance Article on the web 4th July 2003 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- butylstannyl-ferrocene (11) and subsequently 1'-dimethylaminomethylferrocene-1-carbaldehyde (7a) were synthesised from 1,1'-bis(tri-n-butylstannyl)ferrocene, employing [CH 2   NMe 2 ]I and DMF to introduce the amine and then the aldehyde functionalities. In addition, the compound 1'-dimethylaminomethyl-1-lithiumferrocenide was isolated and the 1 H and 13 C 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. Introduction Chloroquine (1, see Fig. 1) has been an effective antimalarial agent since the late 1940s. Unfortunately, in most affected areas, the causative agent Plasmodium falciparum has developed resistance to chloroquine and other quinoline antimalarials. 1 Since malaria affects between 300 and 500 million people each year and is responsible for 1.5 to 2.7 million fatalities, the emergence of quinoline drug resistance is a major problem. 2 To overcome this problem numerous aminoquinolines 3 and aminoquinoline metal complexes 4 have been screened against P. falciparum; of these ferroquine (2a) 5 shows the greatest promise and clinical trials are currently in progress. To establish the role of the iron/ferrocene in ferroquine we have performed preliminary structure–activity relationship studies. 6 As part of this work we have prepared a series of 7-chloro-4-aminoquinolines with amino alkyl side chains con- taining the ferrocene, 7 ruthenocene 8 and phenylene 6 moieties. The synthesis of the ruthenocene analogues resulted in the † Electronic supplementary information (ESI) available: NMR scale synthesis of 7a and 1 H NMR spectrum of 12. See http://www.rsc.org/ suppdata/dt/b3/b303335j/ unexpected synthesis of 4-aminoquinolines with 1,1'-disubsti- tuted ruthenocenes in the side chain e.g. 4b (isoruthenoquine) and 6b. 8 To extend structure–activity relationships, we have now synthesised the corresponding ferrocene complexes 4a (isoferroquine) and 6a. We have also had to develop a new syn- thetic route since ferrocene and ruthenocene differ significantly in reactivity. Results and discussion The key intermediate for the synthesis of isoruthenoquine (4b), and 6b is the complex 7b (see Scheme 1). 8 Unfortunately, the corresponding iron complex 7a is not readily accessible. When the methodology employed to synthesise 7b was applied to the ferrocene system the 1,2-isomer was formed exclusively and not the desired 1,1'-isomer. Although 7a is described in the literature, poor selectivity and low yields were reported. 9 We have now achieved a higher yielding synthesis of 7a by employing 1,1'-bis(tri-n-butylstannyl)ferrocene (9). The key to this route is the selective and sequential removal of the tri-n- butylstannyl groups with n-BuLi in THF at -78 °C. 10 Firstly, 1'-tri-n-butylstannyl-1-lithiumferrocenide (10) is generated and reacted with Eschenmoser’s salt, ([CH 2   NMe 2 ]I), to introduce Fig. 1 Chloroquine (1) and analogues of current interest (2a–6b). DOI: 10.1039/ b303335j 3046 Dalton Trans. , 2003, 3046–3051 This journal is © The Royal Society of Chemistry 2003