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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.

SUBMITTER: Hwang JY 

PROVIDER: S-EPMC3697074 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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

Hwang Jong Yeon JY   Kawasuji Takashi T   Lowes David J DJ   Clark Julie A JA   Connelly Michele C MC   Zhu Fangyi F   Guiguemde W Armand WA   Sigal Martina S MS   Wilson Emily B EB   Derisi Joseph L JL   Guy R Kiplin RK  

Journal of medicinal chemistry 20110926 20


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 analo  ...[more]

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