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

Abstract

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 .

A Validated HPLC-PDA-HRMS Method to Investigate the Biological Stability and Metabolism of Antiparasitic Triterpenic Esters

“…The mixture of 8TTE was isolated from the dichloromethane extract of Keetia leucantha twigs as described by Bero et al [ 9 ] ( Supplementary Materials Figure S5 ). UA-3- O -PP was hemi-synthetized as previously described from ursolic acid [ 11 ] ( Supplementary Materials Figure S6 ). The compounds purity was assessed using an Accela HPLC-PDA system (Thermo Fisher Scientific Inc., Bremen, Germany) at 210 and 310 nm for hemi-synthetic (>97%) and natural (>98%) compounds, respectively as described below.…”

“…in vivo antimalarial activity was identified in Keetia leucantha twigs, supporting their traditional use and triterpenes interest in parasitology [ 9 , 10 ]. Moreover, recent hemi-synthesis of ursane C-3 triterpenic esters highlighted the in vitro and in vivo potential against Trypanosoma brucei of ursolic acid-3- O -phenyl propionate (UA-3- O PP) [ 11 ]. The present study aimed to investigate the stability of these promising antiparasitic triterpenic esters and their potential to target malaria and HAT infections.…”