Conclusions & Prospects

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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. Email: gdegotte@doct.uliege.be 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 (105-330 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 1278.33 2 63.96±4.31 69628.29 3 CH3 26.84±1.81 44604.75 4 CH3CO 9.30±3.03 997.11 5 BnCH2 56.38±2.15 362.18 6 34.94±5.97 2559.69 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) 330.91 587.82 543.04 322..31 279.06 364.60 275.96 287.07 189.91 246.04 135.73 178.40 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. (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).