Progress in controlling malaria has slowed in recent years and the annual death toll remains above 400 000 globally, with most deaths caused by Plasmodium falciparum.
Malaria is a threat to human mankind and kills about half a million people every year. On the other hand, COVID‐19 resulted in several hundred thousand deaths since December 2019 and remains without an efficient and safe treatment. The antimalarials chloroquine (CQ) and its analogue, hydroxychloroquine (HCQ), have been tested for COVID‐19 treatment, and several conflicting evidence has been obtained.
The replacement of one chemical motif with another that is broadly similar is a common method in medicinal chemistry to modulate the physical and biological properties of a molecule (i.e. bioisosterism). In recent years, bioisosteres such as cubane and bicyclo[1.1.1]pentane (BCP) have been used as highly effective phenyl mimics. Herein we show the successful incorporation of a range of phenyl bioisosteres during the open source optimization of an antimalarial series.
Mutations that mediate resistance of Plasmodium falciparum to aminoquinoline antimalarials are selected by prior drug use and may alter parasite fitness, but associations with clinical presentations are uncertain. We evaluated genotypes in samples from a case control study of determinants of severe malaria in Ugandan children 4 months to 10 years of age. We studied 274 cases with severe malaria matched by age and geography to 275 uncomplicated malaria controls and 179 asymptomatic parasitemic controls.
Among several factors behind drug resistance evolution in malaria is the challenge of administering overall doses that are not toxic for the patient but that, locally, are sufficiently high to rapidly kill the parasites. Thus, a crucial antimalarial strategy is the development of drug delivery systems capable of targeting antimalarial compounds to Plasmodium with high specificity.
Either intuition or empiricism must have led to the use of antimalarial drugs to both treat and prevent malaria, pre-dating the identification of the malaria parasite and the mode of its transmission. Josep Masdevall in the XVIII century managed epidemics in Spain through the administration of compounds that included the bark of the cinchona tree. In more recent times, mass drug administration (MDA) was the first form of chemoprevention used against malaria in the early 1900s.
Ozonide antimalarials, OZ277 (arterolane) and OZ439 (artefenomel), are synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum. Here we used a “multi-omics” workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of ozonide-treated P. falciparum infected red blood cells revealed a rapid depletion of short Hb-derived peptides followed by subsequent alterations in lipid and nucleotide metabolism, while untargeted peptidomics showed accumulation of longer Hb-derived peptides.
Malaria is a worldwide parasitic disease, which affects millions of lives every year. Various medications are recommended by WHO for prevention and treatment of malaria. However, adverse events caused by antimalarials were frequently reported, some of which were severe and fatal.
The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria.
A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models.