A Divergent Synthesis\nof Numerous Pyrroloiminoquinone\nAlkaloids Identifies Promising Antiprotozoal Agents

On the basis of a\nstreamlined route to the pyrroloiminoquinone\n(PIQ) core, we made 16 natural products spread across four classes\nof biosynthetically related alkaloid natural products, and multiple\nstructural analogs, all in ≤8 steps longest linear sequence\n(LLS). The strategy features a Larock indole synthesis as the key\noperation in a five-step synthesis of a key methoxy-PIQ intermediate.\nCritically, this compound was readily diverged via selective methylation\nof either (or both) of the imine-like or pyrrole nitrogens, which\nthen permitted further divergence by either <i>O-</i>demethylation\nto <i>o-</i>quinone natural products or displacement of\nthe methoxy group with a range of amine nucleophiles. Based on a single,\nearly report of their potential utility against the malaria parasite,\nwe assayed these compounds against several strains of Plasmodium falciparum, as well as two species of\nthe related protozoan parasite <i>Babesia</i>. In combination\nwith evaluations of their human cytotoxicity, we identified several\ncompounds with potent (low-nM IC<sub>50</sub>) antimalarial and antibabesial\nactivities that are much less toxic toward mammalian cells and are\ntherefore promising lead compounds for antiprotozoal drug discovery.