Malaria is a disease caused by the protozoan parasite Plasmodium. In 2014, it was responsible for ˜438,000 deaths, nearly all of which were caused by P. falciparum [1]. Although a number of highly successful antimalarials have been developed over the past century, drug resistances have rendered the majority ineffective [2]. Our last line of defence against malaria, artemisinin-based combination therapies (ACTs), are now also beginning to fail in South-East Asia. It is likely that artemisinin resistance will intensify and spread throughout Asia and into Africa, potentially causing a public health disaster [3]. Resultantly, there is a dire need for the development of new drugs to replace ACTs.

Natural products have historically been an important source of antimalarial drugs – the plant-derived natural products quinine and artemisinin have formed the backbone of antimalarial chemotherapeutics for hundreds of years [4]. With the aim of discovering new antimalarial drug leads, we chemically investigated the Australian/Papua New Guinean native plant Flindersia pimenteliana F. Muell. (Rutaceae). This genus is particularly rich in alkaloids and is known to contain compounds that are bioactive against chloroquine-resistant P. falciparum [5]. By using semi-preparative HPLC in combination with MS and NMR-guided interpretation, we isolated four new indole alkaloids, three of which are members of a novel compound class (1-4). We also isolated four previously known and potently antimalarial bis-indole alkaloids: flinderoles A (5), B (6), C (7) and dimethylisoborreverine (8).