Synthesis and antimalarial activities of rhenium bioorganometallics based on the 4-aminoquinoline structure

Abstract

A bioorganometallic approach to malaria therapy led to the discovery of ferroquine (FQ, SSR97193). To assess the importance of the electronic properties of the ferrocenyl group, cyclopentadienyltricarbonylrhenium analogues related to FQ, were synthesized. The reaction of [ N-(7-chloro-4-quinolinyl)-1,2-ethanodiamine] with the cyrhetrenylaldehyde complexes (η 5-C 5H 4CHO)Re(CO) 3 and [η 5-1,2-C 5H 3(CH 2OH)(CHO)]Re(CO) 3 produces the corresponding imine derivatives [η 5-1,2-C 5H 3(R)(CH N–CH 2CH 2NH–QN)]Re(CO) 3 R = H 3a; R = CH 2OH 3b; QN = N-(7-Cl-4-quinolinyl). Reduction of 3a and 3b with sodium borohydride in methanol yields quantitatively the amine complexes [η 5-1,2-C 5H 3(R)(CH 2–NH–CH 2CH 2NH–QN)]Re(CO) 3 R = H 4a; R = CH 2OH 4b. To establish the role of the cyrethrenyl moiety in the antimalarial activity of this series, purely organic parent compounds were also synthesized and tested. Evaluation of antimalarial activity measured in vitro against the CQ-resistant strains (W2) and the CQ-susceptible strain (3D7) of Plasmodium falciparum indicates that these cyrhetrene conjugates are less active compared to their ferrocene and organic analogues. These data suggest an original mode-of-action of FQ and ferrocenyl analogues in relationship with the redox pharmacophore.