Semisynthesis of ω-Hydroxyalkylcarbonate Derivatives of Hydroxytyrosol as Antitrypanosome Agents

Abstract

Several lipophilic ω-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 ω-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 μM) and another with a double bond in the alkyl chain (0.4 μM). 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 ω-hydroxyalkylcarbonate and alkylcarbonate derivatives of hydroxytyrosol were also active against T. brucei within a low micromolar range (about 1 μM).

Hydroxytyrosol, Tyrosol and Derivatives and Their Potential Effects on Human Health

“…It was demonstrated that HTyr has antitrypanosomal and antileishmanial activity [94]. HTyr alkylcarbonate derivatives were active against Trypanosoma brucei [95]. Trypanosomiasis and leishmaniasis, infectious diseases caused by protozoan parasites, affect millions of people around the world, especially in tropical and subtropical area, and present one of the major causes of hunger and poverty in sub-Sahara Africa.…”

Polyphenol-Rich Extracts from Agroindustrial Waste and Byproducts: Results and Perspectives According to the Green Chemistry and Circular Economy

“…For example, esterification reactions, coupled with protection and deprotection of hydroxyl groups, have been performed to achieve the formation of ω-hydroxyalkylcarbonate derivatives starting from HTyr (Scheme ). These derivatives showed increased antimicrobial activity against Tripanosoma brucei compared to HTyr.…”

Tailored Functionalization of Natural Phenols to Improve Biological Activity

“…The synthesis of alkyl carbonate derivatives of hydroxytyrosol is strategic to increase hydroxytyrosol antioxidant activity [ 272 ]. Carbonate derivatives have been achieved by a multi-step process in which the chloroformate hydrxytyrosol derivative (having protected phenolic groups) was reacted with alkyl alcohols or diols of different chain lengths [ 272 , 273 ] ( Scheme 24 ). Hydroxytyrosyl carbonates also exhibited higher anti-trypanosome activity against Trypanosoma brucei with respect to the precursor [ 273 ].…”