title: Application of multicomponent reactions to antimalarial drug discovery. Part 2: New antiplasmodial and antitrypanosomal 4-aminoquinoline gamma- and delta-lactams via a 'catch and release' protocol.
abstract: A parallel synthesis of a new series of 4-aminoquinoline gamma- and delta-lactams synthesized via the Ugi 3-component 4-centre multicomponent reaction is described. The basicity of the quinoline nitrogen was exploited in the purification of compounds via a 'catch and release' protocol. Yields ranging from 60% to 77% and purities as high as 96% were obtained. Compound 29, the most active against a chloroquine-resistant W2 strain of Plasmodium falciparum with an IC(50) of 0.096 microM, also inhibited recombinant falcipain-2 in vitro (IC(50)= 17.6 microM). Compound 17 inhibited the growth of Trypanosoma brucei with an ED(50) of 1.44 microM whilst exhibiting a favourable therapeutic index of 409 against a human KB cell line.
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch, South Africa.
authors.forename: Chitalu C
authors.initials: CC
authors.lastname: Musonda
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.forename: Renata C
authors.initials: RC
authors.lastname: Carvalho de Souza
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*; D002460:Cell Line; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D007769:Lactams; C001920:4-aminoquinoline