New class of potent antimalarial drugs found

An international team of scientists has found a new class of molecules that showed a high level of potency against human malaria parasites in animal trials.

The new compounds, known as pyrazoleamides, were effective against Plasmodium falciparum as well as Plasmodium vivax , the two most prevalent parasite species causing human malaria, say Akhil B. Vaidya of the Drexel University College of Medicine in the U.S. and the other scientists in a paper just published in Nature Communications .

Globally, there were about 207 million malaria cases and some 627,000 deaths in 2012, according the World Health Organization’s estimates.

“Many of the existing antimalarial drugs stop working because of resistance development, [and] so it is essential to feed the pipeline with new antimalarial drugs through discovery and development,” remarked Prof. Vaidya in an email.

“The compounds we describe in this paper work very rapidly through a novel mechanism in malaria parasites, and thus would work against drug resistant parasites currently infecting humans.”

At one stage in its complicated lifecycle, the parasite infects red blood cells and replicates inside them. Using a mouse model carrying human red blood cells, the scientists examined the drug’s effect on

P. falciparum , which causes the most dangerous forms of malaria.

As the parasite matures inside the red blood cells, it produces a change in the permeability of the membrane around those cells. That leads to a sharp increase in sodium levels in the red blood cells.

The new pyrazoleamides affect a molecular pump the parasite relies on to control its own sodium levels. As a result, the parasite swells rapidly, followed by what the paper described as “dramatic apparent bursting.”

“However, we believe the mechanisms for parasite demise and clearance are complex,” said Prof. Vaidya in his email. The increased sodium levels inside the parasite could also be providing a premature signal for it to try and leave the red blood cells. “This would be lethal for parasites since they would not have completed the complicated process of assembling all the components necessary for generating infectious progeny called merozoites.” (The merozoites go to infect more red blood cells.)

An added attractive feature of the new compounds was their activity against the mature sexual stages of P. falciparum, the paper noted. The parasite’s male and female forms mate after being ingested by a blood-feeding mosquito. Inhibiting the production of those sexual stages would help prevent onward transmission of the parasite by mosquitoes.

One of the new molecules has been identified for further development as a candidate antimalarial drug.

A novel antimalarial drug now in human clinial trials, which belongs to a different class of chemicals (known as spiroindolones), also targets the malaria parasite's ability to control its sodium levels.