Polyhydroxybenzoic acid derivatives as potential new antimalarial agents

Abstract

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 understand the structure-activity relationships explaining their antiplasmodial effect. Only gallic acid derivatives showed a noticeable potential for further developments. Indeed, they showed a selective inhibitory effect on Plasmodium (IC 50 ~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).

Dimeric polyphenols to pave the way for new antimalarial drugs

“…This could confirm the major role of the phenolic hydroxyl groups, as discussed before, and the intramolecular bonds in the aqueous solubility. 16…”

“…Indeed, in contrast to their corresponding monomers (8,(44)(45), in which only 8 was active on Plasmodium, all the dimers exhibited an equivalent antiplasmodial efficacy. 16 Therefore, the dimer is equally potent, even if the scaffold possesses a 3,4-or 3,5-dihydroxybenzoate moiety. This suggested that the dimerization of these structures created new beneficial interactions with the targets since this effect was not the result of the cumulative activity of two polyhydroxybenzoic acid molecules but instead of one.…”

“…In addition, because of the particular interest developed regarding the pan-assay interference (PAINS) potential of the polyphenolic structures, and the risk of false positives during in vitro assays, 46,47 the antiplasmodial effect of the dimers was confirmed through a microscopy evaluation of the parasitaemia after 48 hours of incubation. 16,48 This method allows a visual evaluation of the parasitic burden during the in vitro experiments. Fortunately, the test compounds have obtained similar IC 50 values with this method to that with the enzymatic revelation.…”

“…Furthermore, the log P increment did not induce a significant cytotoxicity or a loss of hydrosolubility. 16 However, despite this promising profile, the antiplasmodial activity remained limited (IC 50 > 10 μM) and should be further improved since a low to submicromolar in vitro potency is recommended before in vivo experiments. 17 Among the most promising identified polyphenols, ellagic acid (9, Chart 2), a widely distributed molecule, has been known for centuries (1831) and possesses high pharmacological interest.…”

“…Furthermore, the log P increment did not induce a significant cytotoxicity or a loss of hydrosolubility. 16…”