1. Conclusions & Prospects
Design of new antimalarials inspired by ellagic acid through a total synthesis approach.
Gilles Degotte1,2 ; Annabelle Halleux² ; Bernard Pirotte2 ; Pierre Francotte2 ; Michel Frederich1 
1 Laboratory of Pharmacognosy, Centre Interdisciplinaire de Recherches sur le Médicament (CIRM), ULiège – Quartier Hôpital - B36 Tower 4, Avenue Hippocrate 15, 4000 Liège, Belgium.
2 Laboratory of Medicinal Chemistry, Centre Interdisciplinaire de Recherches sur le Médicament (CIRM), ULiège – Quartier Hôpital - B36 Tower 4, Avenue Hippocrate 15, 4000 Liège, Belgium.
Malaria 1
Plasmodium falciparum (mosquito’s bites)
Increasing incidence (219 millions cases)
Decreasing mortality
Documented resistances for all treatments
New molecules needed !
Challenger 2
Ellagic acid (1)
Great in vitro ( nM) & in vivo activities
No side effects
Poor hydrosolubility (9 µg/mL)
No per os use !
Solution 3
Product R
R1/R3
R2/R4
IC50 (µM)
Solubility
(µM) 1 / H
4.05±2.18 2
63.96±4.31 3
CH3
26.84±1.81 4
CH3CO
9.30±3.03
997.11 5
BnCH2
56.38±2.15
362.18 6
34.94±5.97 7
MOM
54.33±10.10
liq. 8
7.61
256.88 9
CH2CH3CH2OPMB
12.10 10
CH2CH3CH2OH
8.17±1.80 11
CH2CH3CH2
1.90±0.90
wip 12
1.75±0.94 13 X 14
i CH3OH, H2SO4 ii Ac2O, H2SO4 iii BnBr, KI, K2CO3, acetone iv K2CO3 , CH3OH, H2O v NaH, MOMCl, DMF vi LiOH, CH3OH, THF, H2O vii 1,3-propanediol-PMB, DMAP, EDCI-HCl, CH2Cl2 viii DDQ, Sorenson’s buffer, CH2Cl2 ix DMAP, EDCI-HCl, CH2Cl2 x THF, IPA/HCl xi CuCL2 , n-BuNH2, CH3OH xii LiOH, CH3OH, THF, H2O
Wip = Work in Progress ; Liq. = liquid
Products 1 2 3 4 5 6 7 8 9 10 11 12
Hemolysis (%)
< 1%
Conc. (µM)
330.91
587.82
543.04
279.06
364.60
275.96
287.07
189.91
246.04
135.73
178.40
Conclusions & Prospects
Great increase of activity (2 fold vs Ellagic acid), not linked to toxic effect on Red Blood cells (100 µg/ml).
But, loss of solubility due to pharmacomodulation of gallic acid (100 fold).
Pharmacophore identification with the dimeric scaffold and free phenolic functions.
Thus, synthesis end and cytotoxicity evaluation = next steps.
References :
1 World Health Organization. World Malaria Report (2018).
2 Soh, P. N. et al. In vitro and in vivo properties of ellagic acid in malaria treatment. Antimicrob. Agents Chemother. 53, 1100–1106 (2009).
3 Hirokane, T., Hirata, Y., Ishimoto, T., Nishii, K. & Yamada, H. A unified strategy for the synthesis of highly oxygenated diaryl ethers featured in ellagitannins. Nat. Commun. 5, (2014).