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Inspired by natural antiprotozoal triterpenes, a library of 12 hemisynthetic 3\u2010<jats:italic>O<\/jats:italic>\u2010arylalkyl esters was derived from ursolic and oleanolic acids through one\u2010step synthesis. Compounds were tested on <jats:italic>Trypanosoma<\/jats:italic>, <jats:italic>Leishmania<\/jats:italic> and the WI38 cell line alongside with a set of triterpenic acids. Results showed that the triterpenic C3 esterification keeps the antitrypanosomal activity (IC<jats:sub>50<\/jats:sub>\u22481.6\u20135.5\u2005\u03bc<jats:sc>m<\/jats:sc>) 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\u2010fluorophenylpropionyl ursolic acids, were tested on an acute mouse model of African trypanosomiasis with significant parasitemia reduction at day 5 post\u2010infection for the dihydrocinnamoyl derivative. Further evaluation on other alkyl\/protective groups should be investigated both <jats:italic>in\u2005vitro<\/jats:italic> and <jats:italic>in\u2005vivo<\/jats:italic>.<\/jats:p>","DOI":"10.1002\/open.202100159","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T11:02:26Z","timestamp":1631185346000},"page":"896-903","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Design, Synthesis and Biological Activity of C3 Hemisynthetic Triterpenic Esters as Novel Antitrypanosomal Hits"],"prefix":"10.1002","volume":"10","author":[{"given":"Laura","family":"Schioppa","sequence":"first","affiliation":[{"name":"Pharmacognosy Research Group Louvain Drug Research Institute (LDRI) UCLouvain  Avenue E. 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