Application of multicomponent reactions to antimalarial drug discovery. Part 2: New antiplasmodial and antitrypanosomal 4-aminoquinoline γ- and δ-lactams via a ‘catch and release’ protocol

A parallel synthesis of a new series of 4-aminoquinoline γ- and δ-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 IC50 of 0.096 μM, also inhibited recombinant falcipain-2 in vitro (IC50 = 17.6 μM). Compound 17 inhibited the growth of Trypanosoma brucei with an ED50 of 1.44 μM whilst exhibiting a favourable therapeutic index of 409 against a human KB cell line.

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