Synthesis and evaluation of 7-substituted 4-aminoquinoline analogues for antimalarial activity.

Abstract

We previously reported that substituted 4-aminoquinolines with a phenyl ether substituent at the 7-position of the quinoline ring and the capability of intramolecular hydrogen bonding between the protonated amine on the side chain and a hydrogen bond acceptor on the amine's alkyl substituents exhibited potent antimalarial activity against the multidrug resistant strain P. falciparum W2. We employed a parallel synthetic method to generate diaryl ether, biaryl, and alkylaryl 4-aminoquinoline analogues in the background of a limited number of side chain variations that had previously afforded potent 4-aminoquinolines. All subsets were evaluated for their antimalarial activity against the chloroquine-sensitive strain 3D7 and the chloroquine-resistant K1 strain as well as for cytotoxicity against mammalian cell lines. While all three arrays showed good antimalarial activity, only the biaryl-containing subset showed consistently good potency against the drug-resistant K1 strain and good selectivity with regard to mammalian cytotoxicity. Overall, our data indicate that the biaryl-containing series contains promising candidates for further study.

DOI: 10.1021/jm200636z

Cite this paper

@article{Hwang2011SynthesisAE, title={Synthesis and evaluation of 7-substituted 4-aminoquinoline analogues for antimalarial activity.}, author={Jong Yeon Hwang and Takashi Kawasuji and David J Lowes and Julie Clark and Michele C. Connelly and Fangyi Zhu and Wendyam A Guiguemde and Martina Sigal and Emily B. Wilson and Joseph L. DeRisi and R. Kiplin Guy}, journal={Journal of medicinal chemistry}, year={2011}, volume={54 20}, pages={7084-93} }