Hydroxytyrosol N-alkylcarbamate conjugates as antitrypanosomal and antileishmanial agents.

Novel lipophilic hydroxytyrosol N-alkylcarbamate conjugates were synthesized by coupling several alkyl isocyanates of different chain lengths with the primary hydroxy group of this natural phenol. These N-alkylcarbamate conjugates were tested as antitrypanosomal and antileishmanial agents, and their cytotoxicity was evaluated against the human MRC-5 and THP-1 cell lines. Five of these N-alkylcarbamate derivatives showed submicromolar IC concentrations against Trypanosoma brucei brucei, with values ranging from 0.2 to 0.8 μM, and three other hydroxytyrosol conjugates showed IC values below 5 μM. Data for the five most active N-alkylcarbamate derivatives indicate a gain in activity relative to hydroxytyrosol of between 115- and 460-fold, and selectivity indices for control/human MRC-5 cells relative to T. b. brucei parasites of between 47- and 140-fold. These N-alkylcarbamate derivatives were also tested against the intracellular amastigote form of Leishmania donovani in infected THP-1 macrophages, where five compounds had IC values less than or equal to 10 μM, with selectivity indices relative to L. donovani of between 3- and 25-fold in MRC-5 cells and between 8- and 60-fold in THP-1 cells. In all of these derivatives, the ortho-diphenolic groups were free. When the hydroxytyrosol derivatives had ortho-diphenolic groups protected by benzyl groups, cytotoxicity against T. b. brucei and L. donovani showed significantly higher IC values, with most cases exceeding 20 μM.