Background

In 2017, the World Health Organization (WHO) estimated that there were 219 million cases of malaria worldwide, an increase of 2 million from the previous year, and as a result, there were 435 thousand deaths, or 1190 per day, mostly young children [1]. Encouragingly, since 2000, these figures have decreased by about 37% worldwide, but a number of recent reports have shown that this level is slowly plateauing, emphasizing that there must not be complacency with the current treatment and prevention strategies [2, 3]. There are five species of the Plasmodium parasite, with Plasmodium falciparum being the most prevalent in Africa and Plasmodium vivax being the most prevalent in countries outside Africa. Almost half the world’s population is at risk of contracting malaria, with Africa having the biggest share of cases and deaths of any continent (∼ 90%).

Over the past few years, a number of reviews have been published which evaluate the potential future of anti-malarial drugs. Of note: Triple-anti-malarial drug combinations were examined in 2014 [4]; a review on the numerous strategies currently used in anti-malarial drug discovery was published in early 2017 [5], and an in-depth primer on all aspects of malaria was published in late 2017 [6]. In early 2018, a review was published highlighting the discovery and development of a number of new anti-malarial drug candidates [7, 8].

This review aims to summarize the past, present and future of compounds used to treat malaria. There is a focus on projects supported by the Medicines for Malaria Venture (MMV), a non-governmental organisation that maintains a website [9] highlighting collaborations from the very early stages of drug discovery and lead optimization (e.g. the Open Source Malaria (OSM) project with which the authors are involved [10]), to the progression of lead compounds through clinical trials (e.g. Cipargamin, which has been developed by Novartis [11]) and all the way to the final stages of bringing a drug to market (e.g. Artesunate for injection, developed by Guilin Pharmaceutical). After a brief survey of past medicines, and those that are currently being used, focus will be put on compounds that are currently in development, and in particular the lead optimization campaigns of each. Since it is such a crucial component of modern anti-malarial drug discovery, this review will end with a survey of the most promising mechanisms of action of those compounds in development.

The scope of this review encompasses compounds described by the MMV survey of current antimalarials, previous reviews on anti-malarial drugs, as well as compounds currently undergoing active clinical trials. The information presented in this review was obtained through the structure searching of the relevant compounds in the SciFinder database. Additional references were found through the Web of Science database (Additional file 1).