title: Design, synthesis and anti-plasmodial evaluation in vitro of new 4-aminoquinoline isatin derivatives.
abstract: A new class of 4-aminoquinoline derivatives based on the natural product isatin scaffold were designed and synthesized for biological evaluation against three strains of the malaria parasite Plasmodium falciparum. These derivatives showed anti-plasmodial IC(50) values in the ranges of 1.3-0.079 and 2.0-0.050muM against a chloroquine-sensitive (D10) and two resistant (K1 and W2) strains of P. falciparum, respectively. In order to determine potential targets for this class of compounds in P. falciparum, selected compounds were also tested against the parasitic cysteine protease falcipain-2. In terms of further development of this class of isatin derivatives, two of the compounds based on a flexible alkyl chain linker and a thiosemicarbazone moiety warrant further investigation as potential anti-plasmodial leads. These two derivatives showed good in vitro activity against K1 and W2 with IC(50) values of 51 and 54nM, respectively, while retaining potency against the D10 strain with IC(50) values of 79 and 95nM, respectively. Generally speaking, the inhibitory potency of all compounds in the series against the parasites did not strongly correlate with inhibitory potency against falcipain-2 for selected compounds tested, which at best was weak to moderate, suggesting other mechanisms of inhibition may also be involved or compounds may be selectively taken up by Plasmodium falciparum.
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Idan
authors.initials: I
authors.lastname: Chiyanzu
authors.forename: Cailean
authors.initials: C
authors.lastname: Clarkson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.forename: Julie
authors.initials: J
authors.lastname: Lehman
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000187:drug effects; D015195:Drug Design; D007510:Isatin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000145:classification / Q000187:drug effects; D011994:Recombinant Proteins / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D011994:Recombinant Proteins; D007510:Isatin; D003546:Cysteine Endopeptidases; C416224:falcipain 2; C001920:4-aminoquinoline