A Divergent Synthesis of Numerous Pyrroloiminoquinone Alkaloids Identifies Promising Antiprotozoal Agents

28 August 2024, Version 1

Abstract

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 analogues, 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 the 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 com-pounds 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 therefore are promising lead compounds for antiprotozoal drug discovery.

Keywords

Total Synthesis

Supplementary materials

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Title
Supporting Information For A Divergent Synthesis of Numerous Pyrroloiminoquinone Alkaloids Identifies Promising Antiprotozoal Agents
Description
Supplemental discussion of reactivity studies, experimental procedures for the synthesis of new compounds, tabulated spectral data supporting the structural assignment of these compounds, NMR spectra for these compounds, X-ray diffrac-tion information for compounds 2, 12, 13, 14, 33, and 46 and biological assay descriptions and results. Also, a summary of previous synthetic efforts in this area.
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