Introduction and Background of the Project

Artemisinin (ART), an active principle of traditional Chinese medicine, has been utilized for treatment of the febrile infectious diseases since ancient times. ART acts rapidly in patients, killing and cleaning the blood stage malaria parasites quickly with minimal side effects. Chemotherapy with ART is also effective against chloroquine-resistant Plasmodium falciparum strains.

One of the drawbacks of ART is the low aqueous solubility, which prompted development of artesunate, a semi-synthetic derivative with improved aqueous solubility. Whilst ART derivatives exert rapid action, the short half-life results in resurgence of malaria unless either multiple doses or a combination medicine are given.

Currently, WHO recommends artemisinin combination therapy (ACT) employing the swift-acting ART-based derivatives combined with different drugs with persisting duration and efficacy. This has brought great success in reducing the negative impact of malaria on global health. However, in recent years, emergence of Plasmodium falciparum with decreased parasite clearance times in response to ART derivative treatment has been reported and combatting this is the immediate threat.

How can your partnership (project) address global health challenges?

To sustain development of ART-based malaria therapies, steady supply of ARTs at stable prices is a concern. Currently, supply of ART mainly relies on extraction from plant Artemisia annua. Because of the complex structure of ART, it is generally believed that totally synthetic approaches will be unlikely to supplant the natural source. Furthermore, artesunate, a water-soluble semi-synthetic derivative of ART with optimum efficacy, entails increased production costs for the additional chemical conversions.

In this project, we designed aza-ARTs by replacing a carbon on the skeleton into a nitrogen in order not only to gain a more facial access to the pharmacophore but also to improve the aqueous solubility and increase structural diversity that may be sufficient to overcome ART-resistant ring stages. Through international collaboration between Hokkaido University, Kitasato University and Medicines for Malaria Venture (MMV), we are developing concise and versatile synthetic process to produce a series of aza-ARTs having desired pharmacological properties, with the intention of generating novel lead compounds against the emerging ART-resistant strains.

What sort of innovation are you bringing in your project?

As a notable feature of the drug design, the small change on atomic level, replacing a single carbon of the ART skeleton with a nitrogen, opens a new vista for achieving major improvements in production efficiency as well as requisite water solubility. Exploiting versatile reactivity of the nitrogen functional group, we have gained expeditious access to the aza-ARTs through single-step assembly of three building blocks and subsequent manipulations to construct the complex skeleton in a small number of steps. Our approach is expected to drastically simplify de novo chemical synthesis of ART derivatives without modifications of the trioxane core, the key substructure responsible for the potent anti-malarial activity.

Since chemical manipulations of ARTs have been mostly limited to the lactone ring, installations of additional functional groups and substituents at other positions as well as skeletal modifications remain largely unexplored. The expeditious and cost-effective synthetic process developing in this project is sufficiently versatile to generate a wide variety of aza-ARTs bearing various substituents and even enables skeletal diversifications for finding new, more potent and longer half-life drug candidates active against ART-resistant malaria. 

Others (including references if necessary)

Jeremy N Burrows, Rob Hooft van Huijsduijnen, Jörg J Möhrle, Claude OeuvrayandTimothy NC Wells^*“Designing the next generation of medicines for malaria control and eradication” Malaria Journal 2013, 12, 187.