Design of new antimalarials inspired by ellagic acid through a total synthesis approach.

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CENTER FOR INTERDISCIPLINARY RESEARCH ON MEDICINES

Design of new antimalarials inspired by ellagic acid

through a total synthesis approach.

Gilles Degotte1,2 _{; Annabelle Halleux²} _{; Bernard Pirotte}2 _; _{Pierre Francotte}2 _{; Michel Frederich}1

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 H 4.05±2.18 1278.33 2 H H H 63.96±4.31 69628.29 3 CH3 H H 26.84±1.81 44604.75 4 CH3 CH3CO CH3CO 9.30±3.03 997.11 5 CH₃ BnCH₂ CH₃CO 56.38±2.15 362.18 6 CH₃ BnCH₂ H 34.94±5.97 2559.69 7 CH₃ BnCH₂ MOM 54.33±10.10 liq. 8 H BnCH₂ MOM 7.61 256.88

9 CH₂CH₃CH₂OPMB BnCH₂ MOM 12.10 liq.

10 CH₂CH₃CH₂OH BnCH₂ MOM 8.17±1.80 liq. 11 CH2CH3CH2 BnCH2 MOM 1.90±0.90 wip 12 CH₂CH₃CH₂ BnCH₂ H 1.75±0.94 wip 13 CH₂CH₃CH₂ BnCH₂ H X X 14 / BnCH2 H X X Products 1 2 3 4 5 6 7 8 9 10 11 12 Hemolysis (%) < 1% < 1% < 1% < 1% < 1% < 1% < 1% < 1% < 1% < 1% < 1% < 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

Wip = Work in Progress ; Liq. = liquid

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).

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,