Effects of cinnamic acid derivatives on in vitro growth of Plasmodium falciparum and on the permeability of the membrane of malaria-infected erythrocytes

Abstract

Cinnamic acid derivatives (CADs) are known inhibitors of monocarboxylate transport across plasma and mitochondrial membranes. All derivatives were found to inhibit the growth of intraerythrocytic Plasmodium faleiparum in culture, which is in correlation with their hydrophobic character. Parasites at the ring and trophozoite stages were equally susceptible to the different derivatives. This result could be attributed to Erythrocytes harboring parasites at mature stages (trophozoites and schizonts) were concentrated from culture by using gelatin flotation (16) or Percoll-alanine gradient centrifugation essentially as described in reference 19, except that sorbitol was replaced with the less toxic amino acid alanine (3% wt/vol). After separation, cells were washed twice in wash medium (i.e., growth medium without plasma) and allowed to recover for 2 h under culture conditions. Cells were counted in a cell counter (Analys Instruments, Stockholm, Sweden), and the percentage of infected cells

Cinnamic Acid/Chloroquinoline Conjugates as Potent Agents against Chloroquine‐Resistant Plasmodium falciparum

“…[14] Interestingly, they observed that NPP inhibitory activity was correlated with the hydrophobic character of the molecules. Additionally, several compounds that have previously been shown to inhibit anion transport pathways, such as 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB; 10), also inhibit NPP.…”

Identity of a Plasmodium lactate/H+ symporter structurally unrelated to human transporters

“…Earlier studies showed that certain compounds, such as phloretin, furosemide and cinnamic acid derivatives, inhibit plasmodial lactate transport 7,8 resulting in cell death 28 . Importantly, the organomercurial p-chloromercuribenzene sulfonate (pCMBS), that inhibits human MCTs by convalently modifying their essential ancillary protein, basigin 29 , does not block Plasmodium lactate transport 7 .…”

Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: Towards the development of potential dual action antimalarials

“…Alternatively, a difference in the respective mechanism of action (MOA) may be operating in addition, or in alternative, to a difference in uptake of HEDICINs versus HECINs: a) due to their dipeptide moiety, HEDICINs might be able to inhibit plasmodial cytosolic proteases like aminopeptidases PfA-M1 and PfA-M17, which function in regulating the intracellular pool of amino acids required for parasite growth and development inside the red blood cell [43,44]; b) HEDICINs anti-plasmodial activity could otherwise be related to the cinnamoyl moiety, as it has been shown that cinnamic acid derivatives inhibit the growth of intraerythrocytic P. falciparum in culture by inhibiting monocarboxylate (e.g. lactate) transport and translocation of other nutrients, as carbohydrates and amino acids required for parasite nourishment [45]; c) finally, HEDICINs anti-plasmodial activity could as well be due to inhibition of the new permeation pathways; meaning that HEDICINs could eventually block the new permeation pathways created in infected RBC (see above, I.c), hampering the uptake of molecules essential to the parasite; it is interesting to notice that amongst our most active molecules as antiplasmodials are those bearing a nitro-aryl moiety, also present in potent new permeation pathways inhibitors such as 5-nitro-2-(phenylalkylamino) benzoic acid derivatives [31].…”