Malaria is an infectious disease causing more than 400,000
deaths per year predominantly among children and pregnant women. While the
disease originates in sub-Saharan Africa and various tropical environments it
is by no means confined to these already extensive areas. Tourism and the
deployment of diplomatic and/or military personnel to these same areas
from around the world allow for the exposure of untold millions of additional
people to this disease making it more and more a global health threat. The eradication
of malaria has been impeded by the rise of resistance to current drugs.
Research involving a new class of antimalarial drug candidates was recently
published in Science Translational Medicine.
Pantothenate (pantothenic acid, vitamin B5) is a water
soluble vitamin that is essential for the malaria parasite's viability due to
its role in the biosynthesis of coenzyme A (CoA). The structures of Pantothenic
acid and Phenethyl-PanAm are shown below:
Phenethyl-PanAm is an example of an early class of
inhibitors of CoA biosynthesis. While these compounds exhibited antimalarial
activity in vitro they could never be developed as clinically useful
agents due to their hydrolytic instability. This class of compounds are
susceptible to hydrolysis by the ubiquitous pantheinase enzymes of the vanin
family. Medicinal chemistry performed by the researchers has led to a new class
of very potent and hydrolytically stable compounds. A few are shown below along
with their IC50 values (nM) against the P.falciparum NF54 asexual blood stage in
vitro:
With regard to stereochemistry the (R) configuration of the
secondary alcohol and the (S) configuration of the methyl group are essential
for potency since epimerization of one or both lead to inactive compounds.
Compound MMV689258 was evaluated in vivo. The compound was well absorbed
upon oral dosing exhibiting 33.6% bioavailability in mice and 63.4% in rats.
This compound was then tested in a humanized mouse model infected with P.falciparum.
At single doses ranging from 25 to 200 mg/Kg given 3 days after infection,
parasitemia was reduced by 77-99.9% at day 7 compared to untreated control
mice. In all of the animal experiments the drug was well tolerated as no
obvious acute adverse effects were noted. Additionally, the drug caused no
detrimental effects on red blood cell counts. This new class of compounds
represent a much needed therapeutic tool in the ongoing fight against Malaria.
The paper can be found here:
