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.
Musonda, Chitalu C;
Gut, Jiri;
Rosenthal, Philip J;
Yardley, Vanessa;
Carvalho de Souza, Renata C;
Chibale, Kelly;
(2006)
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.
Bioorganic & medicinal chemistry, 14 (16).
pp. 5605-5615.
ISSN 0968-0896
DOI: https://doi.org/10.1016/j.bmc.2006.04.035
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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.