Design, Synthesis and Biological Activity of C3 Hemisynthetic Triterpenic Esters as Novel Antitrypanosomal Hits

SCHIOPPA, LAURA; BEAUFAY, CLAIRE; BONNEAU, NATACHA; SANCHEZ, MARIANELA; GIRARDI, CYNTHIA; LEVERRIER, AURÉLIE; ORTIZ, SERGIO; PALERMO, JORGE; POUPAERT, JACQUES H.; QUETIN?LECLERCQ, JOËLLE

ChemistryOpen

European Chemical Society Publishing

Lugar: WEINHEIM; Año: 2021 vol. 10 p. 896 - 903

2191-1363

Research for innovative drugs is crucial to contribute to parasiticinfections control and eradication. Inspired by natural antiprotozoaltriterpenes, a library of 12 hemisynthetic 3-O-arylalkylesters was derived from ursolic and oleanolic acids throughone-step synthesis. Compounds were tested on Trypanosoma,Leishmania and the WI38 cell line alongside with a set oftriterpenic acids. Results showed that the triterpenic C3esterification keeps the antitrypanosomal activity (IC50=1.6?5.5 μm) while reducing the cytotoxicity compared to parentacids. Unsaturation of the ester alkyl chain leads to an activityloss interestingly kept when a sterically hindered group replacesthe double bond or shields the ester group. An ursane/oleananeC3 hydroxylation was the only important feature for antileishmanialactivity. Two candidates, dihydrocinnamoyl and 2-fluorophenylpropionyl ursolic acids, were tested on an acutemouse model of African trypanosomiasis with significant parasitemiareduction at day 5 post-infection for the dihydrocinnamoylderivative. Further evaluation on other alkyl/protectivegroups should be investigated both in vitro and in vivo.