Synthesis and structure-activity relationship of novel indolizinoindolones with<em> in vitro</em> antimalarial activity

Malaria is a vector-borne parasitic disease that continues to pose a serious public health challenge worldwide, despite all effort made towards prevention and control. The etiological agent is parasites of the species Plasmodium. that are transmitted to humans by the bite of infected Anopheles mosquitoes. The emergence of drug-resistant parasites has challenged the goal of eradicating malaria in the near future. In addition, current malaria therapeutics needs to address problems such as relapse and recrudescence events due to persistence of exo-erythrocytic forms in hepatocytes, and erythrocytic forms. Thus, it is still necessary to develop drugs that are effective against drug-resistant strains and active against all stages of the parasite life cycle. Recently, our group has reported the dual-stage antimalarial activity of a series of benzoindolizinoindolones. As part of our continuous effort to identify more potent antiplasmodial compounds, we synthetized 26 novel indolizinoindolones, through stereoselective cyclocondensation of a racemic keto-acid with enantiopure S- or R-tryptophanol, followed by stereocontrolled cyclization on the aromatic ring. Subsequently, we performed structure-activity studies and identified compounds with improved (nanomolar) activity, compared to our previous hit compound, against cultured malaria parasites.Together, this study corroborates our previous results that that identified indolizinoindolones as a promising scaffold for antimalarial drug discovery.