title: Tyrosol and hydroxytyrosol derivatives as antitrypanosomal and antileishmanial agents.
abstract: Trypanosomiasis and leishmaniasis keep being a real challenge for health and development of African countries. Existing treatments have considerable side effects and increase resistance of the parasites. We have measured antitrypanosomal and antileishmanial activity of natural phenols, tyrosol (TYR) and hydroxytyrosol (HT) and several of their esters and metabolites. We found significant IC50 values against Trypanosoma brucei for HT decanoate ester and HT dodecanoate ester (0.6 and 0.36 μM, respectively). This represents a large increase in activity with respect to HT (79 and 132 fold, respectively). Moreover, both compounds displayed a high selectivity index against MRC-5, a non-tumoral human cell line (118 and 106, respectively). Then, we synthesized a focused library of compounds to explore structure-activity. We found the ether and thiourea analogs of HT decanoate ester and HT dodecanoate ester also showed IC50 values against T. brucei in the low micromolar range. In conclusion, the di-ortho phenolic ring and medium size alkyl chain are essential for activity whereas the nature of the chemical bond among them seems less important.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, PTS Granada, Avda. del Conocimiento, 17, 18016, Armilla, Granada, Spain.
authors.forename: Efres
authors.initials: E
authors.lastname: Belmonte-Reche
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, PTS Granada, Avda. del Conocimiento, 17, 18016, Armilla, Granada, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Martínez-García
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, PTS Granada, Avda. del Conocimiento, 17, 18016, Armilla, Granada, Spain; Department of Bioorganic Chemistry, Institute of Chemical Research, CSIC - University of Seville, Avda. Americo Vespucio, 49, 41092, Sevilla, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Peñalver
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, PTS Granada, Avda. del Conocimiento, 17, 18016, Armilla, Granada, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Gómez-Pérez
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, PTS Granada, Avda. del Conocimiento, 17, 18016, Armilla, Granada, Spain; Department of Bioorganic Chemistry, Institute of Chemical Research, CSIC - University of Seville, Avda. Americo Vespucio, 49, 41092, Sevilla, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lucas
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, PTS Granada, Avda. del Conocimiento, 17, 18016, Armilla, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, PTS Granada, Avda. del Conocimiento, 17, 18016, Armilla, Granada, Spain. Electronic address: josepv@ipb.csic.es.
authors.forename: José María
authors.initials: JM
authors.lastname: Pérez-Victoria
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, PTS Granada, Avda. del Conocimiento, 17, 18016, Armilla, Granada, Spain; Department of Bioorganic Chemistry, Institute of Chemical Research, CSIC - University of Seville, Avda. Americo Vespucio, 49, 41092, Sevilla, Spain. Electronic address: jcmorales@ipb.csic.es.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Morales
mesh_terms: D002460:Cell Line; D006801:Humans; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
chemical_list: D014344:Trypanocidal Agents; C005975:3,4-dihydroxyphenylethanol; C011867:4-hydroxyphenylethanol; D010626:Phenylethyl Alcohol
keywords: Antileishmanial; Antitrypanosomal; Hydroxytyrosol; Tyrosol