期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 18, 期 22, 页码 8085-8091出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.09.005
关键词
Malaria; Bioorganometallics; Cyrhetrene-quinoline; Ferroquine
资金
- CONICYT
- MECE-SUP [UCH 0601]
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 (eta(5)-C5H4CHO)Re(CO)(3) and [eta(5)-1,2-C5H3(CH2OH) (CHO)]Re(CO)(3) produces the corresponding imine derivatives [eta(5)-1,2-C5H3(R)(CH=N-CH2CH2NH-QN)]Re(CO)(3) R = H 3a; R = CH2OH 3b; QN = N-(7-Cl-4-quinolinyl). Reduction of 3a and 3b with sodium borohydride in methanol yields quantitatively the amine complexes [eta(5)-1,2-C5H3(R)(CH2-NH-CH2CH2NH-QN)]Re(CO)(3) R = H 4a; R = CH2OH 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. (C) 2010 Elsevier Ltd. All rights reserved.
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