In the global fight against malaria, a devastating disease that claims more than 600,000 lives each year, predominantly children in sub-Saharan Africa, a glimmer of hope has emerged that could turn the tide in the war against this ancient enemy of humanity. Scientists at the University of California, San Francisco (UCSF), have developed an innovative chemical method that could revitalize a promising but failed generation of anti-malarial drugs. Their approach not only solves a key problem that prevented the use of these drugs but also enhances their effectiveness against increasingly resistant parasite strains.

The need for new therapeutic options has never been more urgent. The parasite that causes malaria, Plasmodium falciparum, has developed a terrifying level of resistance to existing, best-available therapies. This resistance, which has been smoldering for years in Southeast Asia, is now spreading unstoppably across Africa, the continent that bears the greatest burden of this disease. "Now that drug resistance has arrived in Africa, countless more lives are at risk," points out Dr. Adam Renslo, a professor of pharmaceutical chemistry at the UCSF School of Pharmacy and the lead author of the study published on August 8 in the journal Science Advances. "These new molecules could give us a much-needed edge in controlling this deadly disease."

A Global Threat: The Spread of Drug Resistance

Malaria has been known for centuries for its cyclical bouts of fever that can be fatal. It is caused by a parasite of the genus Plasmodium, which is transmitted to humans by infected mosquitoes of the genus Anopheles. Once in the human body, the parasites travel to the liver where they multiply before entering the bloodstream and invading red blood cells, causing the symptoms of the disease.

Today's gold standard in treatment, known as artemisinin-based combination therapy (ACT), faces a serious challenge. Artemisinin is a powerful compound isolated from the sweet wormwood plant (Artemisia annua), which has been used for centuries in traditional Chinese medicine. Its combination with other anti-malarial drugs was intended to prevent the development of resistance. However, the parasite has once again shown its incredible ability to adapt.

"For years, we have been monitoring artemisinin resistance in Southeast Asia, but now we are witnessing its spread to Africa, where 95% of cases and 95% of deaths occur," explains Dr. Phil Rosenthal, a professor of medicine at UCSF and co-author of the paper. "Given how long it takes to develop new drugs, there is a general consensus that we need better drugs as soon as possible to circumvent this resistance."

A Historical Battle: From Quinine to Artemisinin

The fight against malaria is long and exhausting. For centuries, the only effective drug was quinine, an alkaloid derived from the bark of the cinchona tree. In the mid-20th century, chemists, inspired by the structure of quinine, developed more powerful synthetic drugs, among which chloroquine stood out. Chloroquine was an extremely successful and inexpensive drug for decades, but over time, the parasite developed resistance, rendering it almost useless in many parts of the world. The global health community was forced to seek new alternatives.

A revolution came with the discovery of artemisinin, for which the Chinese scientist Tu Youyou was awarded the Nobel Prize in 2015. Its unique mechanism of action was effective against chloroquine-resistant parasites. To slow the development of new resistance, artemisinin was paired with other drugs in the aforementioned ACT therapy. This approach proved very successful, but the emergence of resistance to artemisinin as well marked the beginning of a new, dangerous phase in the fight against malaria.

Artefenomel: Promise and Disappointment

In the search for a successor to ACT therapy, artefenomel was developed, a newer derivative inspired by artemisinin. Scientists had high hopes for this compound. It was so potent that it was believed it could cure malaria in a single dose. This would have been a huge advance over ACT, which must be taken for three consecutive days to be effective.

"With a disease like malaria, the ideal is to cure the patient with a single pill or a handful of pills and be done with the therapy," says Renslo. "A multi-day regimen carries the risk of a missed dose, which can lead to treatment failure and encourage the further development of resistance."

However, artefenomel proved to be extremely problematic in clinical trials. Its biggest drawback was its extremely poor solubility in water. Because of this, it could not be formulated into a simple tablet. It had to be administered as a suspension – a powder that is shaken with a liquid and quickly drunk. Such a formulation was impractical and also made it difficult to combine with other drugs in a single tablet. A particular problem arose with children, who often had difficulty retaining the unpleasant liquid, which called into question whether they had received a full, therapeutic dose. Due to these insurmountable difficulties, clinical trials of artefenomel were discontinued in January 2025, leaving a gap in the arsenal of future drugs.

Chemical Elegance: The Solution in Molecular Symmetry

This is where Adam Renslo's team comes in. They realized that the root of the problem might lie in the very structure of the artefenomel molecule. Specifically, the molecule was highly symmetrical. It is well known in chemistry that highly symmetrical molecules tend to pack into very stable and dense crystal lattices. These crystals dissolve very slowly, much like a lump of sugar dissolves more slowly than fine crystals. This low solubility directly affected the drug's bioavailability – the amount that reaches the bloodstream and gets to the target, in this case, the malaria parasite.

Their hypothesis was elegant in its simplicity: if symmetry is the problem, the solution is asymmetry. The scientists theorized that a less symmetrical version of artefenomel could avoid tight "packing" into crystals and therefore dissolve more easily. They went to the lab and applied a kind of "chemical trick" – they rearranged the atoms within the existing artefenomel molecule to disrupt its symmetry without disturbing the part of the molecule responsible for killing the parasite. Their first successful attempt at synthesizing a new, asymmetrical molecule immediately confirmed the correctness of the theory. When they added it to a water-like solution, the new molecule dissolved instantly, unlike the milky suspension created by the original artefenomel.

Towards a New Generation of Drugs

The team continued to fine-tune the new molecules, creating several different versions. A rigorous testing process followed. First, they tested their effectiveness against malaria parasites in cell cultures in the laboratory. Then they moved on to testing in animal models. The final and most important test was to confront the optimized compound with artemisinin-resistant parasites isolated from the blood samples of malaria patients in Uganda.

The results were extraordinary. The optimized asymmetrical compound passed all tests with flying colors. It proved to be as potent as the original artefenomel but significantly more effective than artemisinin itself against resistant strains of the parasite. Crucially, it retained its newfound, excellent solubility, which opens the way for the development of a simple tablet that could be easily combined with other anti-malarial drugs.

This breakthrough is not just a technical solution to a pharmaceutical problem; it represents a new strategy in drug design. It shows how clever, targeted modifications at the molecular level can overcome physical barriers that stand in the way of effectiveness. "We are optimistic that a simple chemical change like this can pave the way for an effective successor to artemisinin," concludes Renslo, "one that will be cheap to produce and easy to combine with other anti-malarial drugs." This work, funded by the National Institutes of Health (NIH), offers new hope that science may once again outsmart the parasite in this long and exhausting battle for human lives. You can read more about the global efforts to combat this disease on the World Health Organization's website.