Semisynthesis of omega-Hydroxyalkylcarbonate Derivatives of Hydroxytyrosol as Antitrypanosome Agents

Abstract

Several lipophilic omega-hydroxyalkylcarbonate hydroxytyrosol derivatives and also their corresponding dimeric derivatives have been synthesized, coupling the primary hydroxy group of this phenolic compound with several terminal diols of different chain lengths, by the use of a carbonate linker. The trypanocidal activity and cytotoxicity of these omega-hydroxyalkylcarbonate derivatives of hydroxytyrosol and known alkylcarbonate derivatives of hydroxytyrosol were assessed. Three of the hydroxytyrosol alkylcarbonate derivatives were active against Trypanosoma brucei: two with an alkyl chain of average size (0.2 and 0.5 mu M) and another with a double bond in the alkyl chain (0.4 mu M). These values suggest an increase in activity with respect to hydroxytyrosol (264-, 90-, and 116-fold, respectively). Furthermore, these compounds showed high selectivity indices against MRC-5, a nontumor human cell line (62, 71, and 39, respectively). Some other omega-hydroxyalkylcarbonate and alkylcarbonate derivatives of hydroxytyrosol were also active against T. brucei within a low micromolar range (about 1 mu M).