Authors

C Beaufay³; J Bero³; N Bonneau³; C Girardi³; M Sanchez¹; A Leverrier¹; R Frédérick²; J Palermo¹; J Quetin-Leclercq³;  ¹ Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina;  ² UCL/LDRI/CMFA, Belgium;  ³ UCL/LDRI/GNOS, Belgium

Discussion

Human African trypanosomiasis, so called sleeping sickness, is a parasitic infection endemic in 36 African countries with about 3,000 new cases registered each year and 13 million people at risk of infection in 2015 [1]. This neglected disease, due to Trypanosoma brucei, may evolve into a neurological disease and be lethal if non treated. A promising source of new active compounds, as alternative to limited and toxic actual medications, could be natural compounds [2, 3] such as bioactive pentacyclic triterpenes [4]  some of them being  identified in a Beninese traditionally used plant, Keetia leucantha [5].

The purpose of this work was 1-to study structure-activity relationships with other triterpenic derivatives identified in the Keetia gender, semi-synthetized or commercialized to define structural key positions and improve selective activity and 2- to evaluate the in vivo activity of plant extract and the most promising compounds. Tests were performed on Trypanosoma brucei brucei (strain 427) and selectivity measured on the mammalian WI38 cells.

Preliminary structure-activity relationships allowed us to observe that, for acids, the more hydroxylated, the less active they are with potential impact of configuration (α2 versus β23). A ketone and a shift of the double bond lead to a decrease of activity. Furthermore, ursane derivatives seem more active than oleanane ones as suggested in literature. For esters, the position of esterification seems to be important. Indeed, C-28 esters are significantly less active than their corresponding acids. C-27 esters isolated from Keetia leucantha are more active than acids but activities still stay moderate to low. For esterification on position 3, a similar or higher activity is mostly observed with even a significant increase for oleanane esters. However, ursolic acid and two esters, hydrocinnamic and ortho-fluorophenylpropionic, as well as Keetia leucantha twigs dichloromethane extract didn’t show any parasiteamia inhibition or survival impact in an aggressive in vivo model. We have now to evaluate the activity of these compounds and other derivatives on Plasmodium and Leishmania.