Pharmaceutical Roots: Malaria, from Bugs to Drugs

Pharmaceutical Roots is a content series from LGC Mikromol investigating and outlining the natural origins of pharmaceutical substances, and offering a deeper dive into their uses, risks, and mechanisms of action. In the first article of our new Bugs to Drugs sister series, we turn the  spotlight on almost 350 years of developing medicines to fight malaria – still the world’s most deadly parasitic disease.

Introduction

Malaria is a life-threatening parasitic infection that imperils around half of the world’s population. A rival to tuberculosis as the most lethal disease in history, it was responsible for 247 million cases, and an estimated 619,000 deaths in 2021 – 96% of them in Africa. One of many deadly diseases transmitted by mosquitoes, malaria is also a concern in other tropical regions of the world, including Asia, Central and South America, parts of the Middle East, and the Pacific.

Malaria in humans is caused by infected female Anopheles mosquitoes spreading five Plasmodium parasite species through their bites. Of the five species, P. falciparum and P. vivax pose the greatest threat, with P. falciparum the dominant strain in Africa and P. vivax the most widespread elsewhere. According to the World Health Organisation (WHO), children under five, pregnant women, HIV/AIDS patients, and migrant workers are particularly at risk of contracting severe malaria.

Malaria develops when parts of the Plasmodium parasite called sporozoites travel to the liver via the bloodstream, where they invade hepatocytes, then grow and divide for two to ten days. The invaded hepatocytes eventually break down - releasing a mature form of Plasmodium cells into the bloodstream, which rapidly invade individual red blood cells. Particularly in the case of P. falciparum, the disease can prove fatal if left untreated - progressing “to severe illness and death within a period of 24 hours.”

Although many medications have been formulated to combat malaria, controlling the disease has been made more complex by factors including drug resistance and adverse reactions. Both P. falciparum and P. vivax have demonstrated worrying levels of resistance to modern treatments – a development that has extended the usefulness of quinine, the world’s oldest antimalarial, despite its own side-effects and “sporadic observations of quinine resistance.” Currently, WHO bases its global antimalarial strategy on three main pillars: vector control (including insecticide-treated nets and indoor spraying), medicines (taken either singly or in combination), and vaccinating children in areas of increased malaria risk.

Cinchona and quinine: the first antimalarials

Traditionally used to fight fever by indigenous Peruvians, extracts from Cinchona tree bark were first employed by Europeans to treat malaria from the early 1600s. Also known as ‘Jesuit’s bark’, or ‘sacred bark’ due to its use by Christian missionaries, cinchona bark was ground to a fine powder, then mixed with liquid – usually wine – before being drunk. In 1820, the French chemists Pierre Joseph Pelletier and Joseph Caventou extracted quinine from it, and purified quinine thereafter became the standard treatment for malaria. This quinine extract also represented the first successful use of a chemical compound to treat an infectious disease: in trials conducted between 1866-1868, quinine and three other cinchona alkaloids - quinidine, cinchonine and cinchonidine – were all greater than 98 per cent successful in curing the symptoms of 3,600 malarial patients. 

The 1854 discovery by Scottish physician William Balfour Baikie that quinine could be used to prevent malaria, and not just as an after-treatment, was significant both for the history of medicine and history in general. As the Royal Botanic Gardens in London states: “Prior to this, death rates of Europeans on west African expeditions were extraordinarily high… and Baikie’s actions had repercussions across the world. Seeds and plants were taken from South America to plantations in India and Java.... Quinine, and the Cinchona tree, now became a vital tool for the control and expansion of empires.”

Chloroquine

Geopolitics also featured strongly in the story of chloroquine – an early synthetic version of quinine. By 1934, German scientists had produced a new class of antimalarials, including Resochin and Sontochin (3-methyl-chloroquine), with a patent being granted to the giant IG Farben conglomerate just before the Second World War. However, vital knowledge about the drugs fell into Allied hands in 1943, when French soldiers “happened upon a stash of German-manufactured Sontochin in Tunis and handed it over to the Americans”. After making adjustments to enhance the effectiveness of the captured drug and naming it chloroquine, the US scientists only belatedly realised that their new compound was chemically identical to Resochin.

After 1945, chloroquine became one of the main weapons in WHO’s global eradication malaria campaign, although chloroquine resistant P. falciparum subsequently arose in four separate locations across the world between 1957 and 1983. Hydroxychloroquine, a less toxic metabolite of chloroquine is also used to treat malaria and was the 126^th most prescribed medicine in the US in 2020.

Proguanil

Developing reliable antimalarials was vital to the Allied forces fighting in malarial zones during World War Two – particularly as many existing treatments were made in Germany, and because Japan’s entry to the war denied Britain, France and the US access to Asian quinine plantations. Proguanil, a pyrimidine derivative, emerged from US-funded war research at the British firm ICI, carried out by Frank Rose and Frank Curd. The pair chose to focus on pyrimidines because they were relatively simple to synthetise, and because Rose was already familiar with them from his earlier work on sulphonamides. Having noticed a geometric pattern in the effective analogues, they wondered if they could reproduce their biological activity with even simpler molecules, and without the pyrimidine ring. After this, they focused on biguanides - then known as diguanides – and arrived at a modified antimalarial compound named paludrine, which was both a curative and a prophylactic. Introduced in 1945, the new compound - later known as proguanil, and by the brand name Malarone - became one of the world’s most widely-used antimalarial drugs.

Atovaquone

Commonly used in combination with Malarone against uncomplicated malaria, or to prevent P. falciparum developing in travellers, the hydroxynaphthoquinone antimicrobial atovaquone can also trace its origins back to the hundreds of thousands of potential antimalarial compounds studied during World War Two. Initially abandoned after displaying poor absorption and rapid metabolism in human trials, work on developing the drug restarted in both the 1960s and 1980s. In combination, proguanil acts via the inhibition of dihydrofolate reductase, and the synthesis of pyrimidines needed for nucleic acids, while atovaquone inhibits the malarial cytochrome bc₁ complex in the mitochondrial electron transport chain - leading to blockage of nucleic acids and adenosine triphosphate synthesis. Using both drugs means that disruption of the mitochondrial membrane occurs - leading to apoptosis due to the indirect inhibition of dihydroorotate dehydrogenase. The combination also causes side effects less often than the alternative antimalarials doxycycline and mefloquine.

Artemisinin-Based Combination Treatments (ACTs)

Regarded as the best current therapeutics for treating uncomplicated falciparum malaria, ACTs also owe their origins to the Vietnam War. In 1967, after being lobbied by North Vietnam for help in cutting the number of communist troops incapacitated by malaria, China launched the secret research mission Project 523. The woman in charge of the covert research, pharmacologist Tu Youyou, scoured ancient texts for potential remedies and eventually settled on artemisinin – a peroxide-containing lactone extracted from the sweet wormwood plant (Artemisia annua). Tu - who later became the first mainland Chinese to receive a Nobel Prize in a science category - also developed a low temperature extraction process to preserve the active ingredient, and even volunteered to be its first human test subject. Although problems accessing ACTs continue to hinder the global effort to conquer malaria, more than one billion artemisinin-based courses were successfully administered in the first 15 years of the 21^st century, saving many millions of lives.

Artemether, a methyl ether derivative of artemisinin, is commonly used to treat infections caused by P. falciparum and unidentified Plasmodium species, including infections acquired in chloroquine-resistant areas. After artemether is activated by complexing with iron in the haem ingested by the parasite, the dihydroartemisinin compound that results produces free radicals and reactive oxygen species that cause disruption to the parasite's Ca2+ transport- and other cellular functions. The combination of artemether and the blood schizonticide lumefantrine - which has a much longer half-life and may clear residual parasites by disrupting their haem detoxification pathways - also reduces resistance.