Polyhydroxybenzoic acid derivatives as potential new antimalarial agents

With more than 200 million cases and 400,000 related deaths, malaria remains one of
the deadliest infectious diseases of 2021. Unfortunately, despite the availability of
efficient treatments, we have observed an increase in people infected with malaria
since 2015 (from 211 million in 2015 to 229 million in 2019). This trend could partially
be due to the development of resistance to all the current drugs. Therefore, there is an
urgent need for new alternatives. We have, thus, selected common natural scaffolds,
polyhydroxybenzoic acids, and synthesized a library of derivatives to better under-
stand the structure–activity relationships explaining their antiplasmodial effect. Only
gallic acid derivatives showed a noticeable potential for furtherQ3 developments. Indeed,
they showed a selective inhibitory effect on Plasmodium (IC50 ~20 μM, SI > 5) often
associated with interesting water solubility. Moreover, this has confirmed the critical
importance of free phenolic functions (pyrogallol moiety) for the antimalarial effect.
Methyl 4-benzoxy-3,5-dihydroxybenzoate (39) has, for the first time, been recognized
as a potential lead for future research because of its marked inhibitory activity against
Plasmodium falciparum and its significant hydrosolubility (3.72 mM).