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

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 16; pp. 5605 - 5615
• Main Authors: Musonda, Chitalu C., Gut, Jiri, Rosenthal, Philip J., Yardley, Vanessa, Carvalho de Souza, Renata C., Chibale, Kelly
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.08.2006; Elsevier Science
• Subjects: 4-Aminoquinolines; Aminoquinolines - chemical synthesis; Aminoquinolines - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarial activity; Antimalarials - chemical synthesis; Antimalarials - pharmacology; Antiparasitic agents; Antitrypanosomal activity; Biological and medical sciences; Cell Line; Falcipain-2; Humans; Lactams; Lactams - chemical synthesis; Lactams - pharmacology; Medical sciences; Multicomponent reaction; Parallel synthesis; Parasitic Sensitivity Tests; Pharmacology. Drug treatments; Plasmodium falciparum; Plasmodium falciparum - drug effects; Polymer-supported reagents; Structure-Activity Relationship; Trypanosoma brucei; Trypanosoma brucei rhodesiense - drug effects; Ugi reaction; Antimalarial activity; Parallel synthesis; Multicomponent reaction; 4-Aminoquinolines; Antitrypanosomal activity; Ugi reaction; Polymer-supported reagents; Falcipain-2; Lactams; Antimalarial; Growth; Chloroquine; Lactam; Combinatorial chemistry; Pyrrolidine derivatives; Research and development; Antiprotozoal agent; Plasmodium falciparum; Structure activity relation; Inhibition; Chemical synthesis; Trypanosoma brucei; Tumor cell; Kinetoplastida; Human; Protozoa; Apicomplexa; Quinoline derivatives; Epidermis; In vitro; Resistance; Cell line; KB cell line; Parasiticide; Solid phase
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.04.035

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 IC 50 of 0.096 μM, also inhibited recombinant falcipain-2 in vitro (IC 50 = 17.6 μM). Compound 17 inhibited the growth of Trypanosoma brucei with an ED 50 of 1.44 μM whilst exhibiting a favourable therapeutic index of 409 against a human KB cell line.