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What began your hunt for antimalarial drugs?
In the 1990s malaria cases were increasing in Brazil and the rest of the world. The natural antimalarial, artemisinin, from the sweet wormwood plant (Artemisia annua) offered great hope, but the new generation of drugs was being developed only semi-synthetically: artemisinin had to be isolated from plants, then transformed into derivatives using synthetic reactions.

This got me interested in plants as sources of antimalarial compounds. After I got a job in Manaus, in the middle of the Brazilian Amazon, I began to focus on plants as the best potential source.

Why is it so important to find new weapons against malaria?
Approximately 200 million people get malaria and just under a million people die from it each year worldwide. There is still no effective, affordable vaccine on the horizon, and malaria parasites become resistant to the drugs over time. New therapies have been introduced in recent times by combining existing drugs, but no actual new antimalarial substances have been brought into clinical practice in more than 20 years.

What has been the most surprising thing you鈥檝e encountered while searching for new plants?
When I go to the interior of the Amazon, after a day or two eating the staple meal of fish and cassava, I often get a stomach ache. One morning, after being up since dawn collecting an antimalarial plant, my guide offered me a cup of coffee. I declined due to my stomach. He looked at me in disbelief, and told me the very plant we had collected that morning would be good for my problem. He quickly prepared a mild remedy. I took it, and it immediately cleared up my stomach ache.

Ironically, this plant, caferana (Picrolemma sprucei) is known as 鈥渇alse coffee鈥�. I knew of its extreme bitterness from working with it for antimalarial infusions. And its use in different doses for treating gastric ailments, malaria infections, and intestinal worms had been written up in the literature. Standing there in the forest, it was a powerful reminder of the value of the practical knowledge of a person who grew up there.

When looking for plants with medicinal qualities, do you often turn to local knowledge?
Malaria has been in Brazil for about 500 years, and in that time local populations have come to use plants of all types to treat fevers, malaria and related problems. And studies confirm that the people of the Amazon region have effectively identified plant species with antimalarial properties. In choosing which species to study, traditional use of the plants is actually the most important criteria.

What types of medications have already been derived from folk remedies?
The bark of a species of Cinchona plant was first identified by indigenous people in the Andean region as being useful against malaria. In the 19th century, quinine was isolated from Cinchona bark extracts, which eventually led to the development of synthetic chemicals such as chloroquine in the early 20th century: a new range of antimalarials was born.

Similarly, in the 1970s, artemisinin was isolated in China from sweet wormwood, long used in traditional Chinese medicine. As a rule of thumb, approximately one-third of traditionally used antimalarial plants are in fact active against the parasite, but less than 1 per cent of plants collected randomly will be.

So there may be more medicinal plants that have long been used by local populations 鈥� plants hiding in plain sight?
Yes, it鈥檚 very possible, even likely. Plant extracts and isolated components from the Amazon have not yet been systematically studied for antimalarial activity 鈥� and there are many plants to choose from. So yes, right under our noses 鈥� or over our heads 鈥� are the plants containing the next antimalarial drug idea from the Amazon.

鈥淧lants under our noses 鈥� or over our heads 鈥� hold the key to new antimalarials鈥�

Describe your average plant-hunting day.
In the late 1990s, we planned expeditions into the forest to collect plants. This is straight-forward in the field, but can be technically complicated: for positive identification, you need to locate plants when they are in flower or have fruit, which obviously is not always possible at any given time.

Then, in 1997, the published a field-guide to its forest reserve. At that point we began to work with those identified species. To this day, we still try to use those mapped plants as much as possible.

So now plant collection starts with a visit to the in Manaus to get the coordinates of the species of interest, then it鈥檚 a 30-minute drive to the reserve and at most a day in the forest. Of course, most of our work is in the lab; collection is only a small part of what we do.

So, back in the lab, how do you test the plants?
Initially, extracts are prepared in ways that are as analogous to traditional practice as possible. Then the malaria parasite (Plasmodium falciparum), is exposed to these extracts in different concentrations. If the extract inhibits parasite growth in a significant way, we may further break it up chemically to try to isolate its components. Once these isolated compounds have been identified, we test them too.

When does the synthetic chemistry come in?
Promising compounds are put through chemical reactions that modify their structures and generate new semi-synthetic compounds. These often have better pharmacological properties 鈥� greater stability, more potency against the malaria parasite, less toxicity to cells and so on 鈥� than the natural products they are prepared from. The derivatives are tested in vitro, and if they show promise, in malaria-infected mice.

This all sounds very time-consuming. How many species have you looked at so far?
Collection, identification, drying and processing of plants, preparation of extracts and so on can take a month for a single plant and up to two years when working on multiple plants at the same time. So far, we have done all of this for about 75 plant species. We are also constantly reviewing the literature on traditionally used antimalarial plants as preparation for future investigation.

Any promising leads so far?
We think so. There is a shrub locally known as caapeba (Pothomorphe peltata) that commonly grows along roadsides and the edge of forests. From its roots, we have isolated a compound, 4-nerolidylcatechol (4-NC), that kills the malaria parasite in vitro. It is unstable though, and was not as potent when given to mice infected with malaria. But it was also not toxic, even at high doses.

To generate stable compounds, we prepared semi-synthetic derivatives of 4-NC. One we tested in mice was about 60 times more potent than the original 4-NC, with no signs of acute toxicity. Now we are synthesising the 4-NC derivatives on a larger scale so that we can run bigger studies.

How does this compound fight malaria?
We are working to explore the underlying mechanisms. We now know that derivatives of 4-NC interfere with the malaria parasite鈥檚 ability to biosynthesise metabolites that help it survive in the human body. For that reason, we believe that semi-synthetic derivatives of 4-NC have real potential as antimalarials. What鈥檚 more, the compound itself is abundant in the roots of the caapeba. We estimate that systematic cultivation would make it possible to produce about 27 kilograms of 4-NC per hectare 鈥� potentially enough to treat many thousands of cases of malaria.

This article appeared in print under the headline 鈥淭he medicine hunter鈥�