Synthesis and Evaluation of 7-Substituted 4-Aminoquinoline Analogues for Antimalarial Activity

详细信息    查看全文

• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 27, 2011
• 年：2011
• 卷：54
• 期：20
• 页码：7084-7093
• 全文大小：1388K
• 年卷期：v.54,no.20(October 27, 2011)
• ISSN：1520-4804

文摘

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鈥檚 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.