A Divergent Synthesis of Numerous Pyrroloiminoquinone Alkaloids Identifies Promising Antiprotozoal Agents

• Published in: Journal of the American Chemical Society Vol. 146; no. 43; pp. 29883 - 29894
• Main Authors: Barnes, Griffin L., Magann, Nicholas L., Perrotta, Daniele, Hörmann, Fabian M., Fernandez, Sebastian, Vydyam, Pratap, Choi, Jae-Yeon, Prudhomme, Jacques, Neal, Armund, Le Roch, Karine G., Ben Mamoun, Choukri, Vanderwal, Christopher D.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 30.10.2024
• Subjects: Alkaloids - chemical synthesis; Alkaloids - chemistry; Alkaloids - pharmacology; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Humans; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium falciparum - drug effects; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Pyrroloiminoquinones - chemical synthesis; Pyrroloiminoquinones - chemistry; Pyrroloiminoquinones - pharmacology; Structure-Activity Relationship
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.4c11897

On the basis of a streamlined route to the pyrroloiminoquinone (PIQ) core, we made 16 natural products spread across four classes of biosynthetically related alkaloid natural products, and multiple structural analogs, all in ≤8 steps longest linear sequence (LLS). The strategy features a Larock indole synthesis as the key operation in a five-step synthesis of a key methoxy-PIQ intermediate. Critically, this compound was readily diverged via selective methylation of either (or both) of the imine-like or pyrrole nitrogens, which then permitted further divergence by either O-demethylation to o-quinone natural products or displacement of the methoxy group with a range of amine nucleophiles. Based on a single, early report of their potential utility against the malaria parasite, we assayed these compounds against several strains of Plasmodium falciparum, as well as two species of the related protozoan parasite Babesia. In combination with evaluations of their human cytotoxicity, we identified several compounds with potent (low-nM IC50) antimalarial and antibabesial activities that are much less toxic toward mammalian cells and are therefore promising lead compounds for antiprotozoal drug discovery.