title: 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.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States.
authors.forename: Jong Yeon
authors.initials: JY
authors.lastname: Hwang
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawasuji
authors.forename: David J
authors.initials: DJ
authors.lastname: Lowes
authors.forename: Julie A
authors.initials: JA
authors.lastname: Clark
authors.forename: Michele C
authors.initials: MC
authors.lastname: Connelly
authors.forename: Fangyi
authors.initials: F
authors.lastname: Zhu
authors.forename: W Armand
authors.initials: WA
authors.lastname: Guiguemde
authors.forename: Martina S
authors.initials: MS
authors.lastname: Sigal
authors.forename: Emily B
authors.initials: EB
authors.lastname: Wilson
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Derisi
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004351:Drug Resistance; D006801:Humans; D008567:Membranes, Artificial; D010539:Permeability; D010963:Plasmodium falciparum / Q000187:drug effects; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D008567:Membranes, Artificial