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

Jong Yeon Hwang, Takashi Kawasuji, David J. Lowes, Julie A. Clark, Michele C. Connelly, Fangyi Zhu, W. Armand Guiguemde, Martina S. Sigal, Emily B. Wilson, Joseph L. Derisi, R. Kiplin Guy

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)7084-7093
Number of pages10
JournalJournal of medicinal chemistry
Volume54
Issue number20
DOIs
StatePublished - Oct 27 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Synthesis and evaluation of 7-substituted 4-aminoquinoline analogues for antimalarial activity'. Together they form a unique fingerprint.

  • Cite this

    Hwang, J. Y., Kawasuji, T., Lowes, D. J., Clark, J. A., Connelly, M. C., Zhu, F., Guiguemde, W. A., Sigal, M. S., Wilson, E. B., Derisi, J. L., & Guy, R. K. (2011). Synthesis and evaluation of 7-substituted 4-aminoquinoline analogues for antimalarial activity. Journal of medicinal chemistry, 54(20), 7084-7093. https://doi.org/10.1021/jm200636z