showed that the methylene group between piperazine and benzylic ring Bn2 as well as the cyclic diamine had a crucial role in the 3-benzylmenadione's (4a) activity. Despite the IC50 value of the 4'-tert-butylbenzyl derivatives being promising, it also presented some drawbacks such as its high lipophilicity (ClogP = 8.09) but also the high cytotoxicity (IC50 = 17.7 µM). In order to improve these features and thus access to more sustainable drug candidates, the introduction of functional diversity on the molecular scaffold was considered. The compounds 4c to 4h, substituted on the C-4' position with various electron-donating and -withdrawing groups on the benzylic ring Bn2 displayed a decrease in antitrypanosomal activity with an IC50 value over 5 µM. Besides, in order to decrease the lipophilicity of the main scaffold, the introduction of N-heteroaromatics was also realized (6a-d and 9a-d). A decrease of cytotoxicity as well as lipophilicity could definitely be observed, yet no trypanocide effect was visible. The trifluoromethylated pyridyl and pyrimidyl derivatives were used because of their easier accessibility than their tert-butyl analogues and the similar properties between CF3 and tBu, both being bioisosteres. Only 9a from the 3-N-heteroaromatic menadione series 9