Open AccessDesign, Synthesis and Biological Activity of C3 Hemisynthetic Triterpenic Esters as Novel Antitrypanosomal Hits
Author(s) -
Schioppa Laura,
Beaufay Claire,
Bonneau Natacha,
Sanchez Marianela,
Girardi Cynthia,
Leverrier Aurélie,
Ortiz Sergio,
Palermo Jorge,
Poupaert Jacques H.,
QuetinLeclercq Joëlle
Publication year - 2021
Publication title -
chemistryopen
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.644
H-Index - 29
ISSN - 2191-1363
DOI - 10.1002/open.202100159
Subject(s) - antiprotozoal , chemistry , alkyl , trypanosoma cruzi , terpene , stereochemistry , abietane , in vivo , organic chemistry , in vitro , biochemistry , diterpene , biology , parasite hosting , microbiology and biotechnology , world wide web , computer science
Research for innovative drugs is crucial to contribute to parasitic infections control and eradication. Inspired by natural antiprotozoal triterpenes, a library of 12 hemisynthetic 3‐ O ‐arylalkyl esters was derived from ursolic and oleanolic acids through one‐step synthesis. Compounds were tested on Trypanosoma , Leishmania and the WI38 cell line alongside with a set of triterpenic acids. Results showed that the triterpenic C3 esterification keeps the antitrypanosomal activity (IC 50 ≈1.6–5.5 μ m ) while reducing the cytotoxicity compared to parent acids. Unsaturation of the ester alkyl chain leads to an activity loss interestingly kept when a sterically hindered group replaces the double bond or shields the ester group. An ursane/oleanane C3 hydroxylation was the only important feature for antileishmanial activity. Two candidates, dihydrocinnamoyl and 2‐fluorophenylpropionyl ursolic acids, were tested on an acute mouse model of African trypanosomiasis with significant parasitemia reduction at day 5 post‐infection for the dihydrocinnamoyl derivative. Further evaluation on other alkyl/protective groups should be investigated both in vitro and in vivo .