Development of new heterocyclic leads against malaria

Abstract

Malaria continues to pose a significant global health and socio-economic burden on those
regions where it is endemic. Despite substantial investment in the delivery of artemisinin-based
combination therapies, causing a fall in malaria mortality, recent data suggest that this parasitic
disease still imposes a significant impact. A major problem is the narrow drug discovery
pipeline, made worse by reports of artemisinin resistance.

In recent years, high-throughput screening of natural products derived from plants and marine
organisms has led to the discovery of potent anti-malarial indole alkaloids (such as
dihydrousambarensine), many of which contain an indoloisoquinoline core.

Building on previously discovered methodology in our group, we have developed a series of
novel, enantiomerically pure, synthetic indoloisoquinoline and their potential as anti-malarial
leads was assessed. The structure-activity relationship of these compounds was investigated in
several areas and a lead compound was generated with an activity close to that of a known
anti-malarial natural product dihydrousambarensine.