title: Prospects of an alternative treatment against Trypanosoma cruzi based on abietic acid derivatives show promising results in Balb/c mouse model.
abstract: Chagas disease, caused by the protozoa parasite Trypanosoma cruzi, is an example of extended parasitaemia with unmet medical needs. Current treatments based on old-featured benznidazole (Bz) and nifurtimox are expensive and do not fulfil the criteria of effectiveness, and a lack of toxicity devoid to modern drugs. In this work, a group of abietic acid derivatives that are chemically stable and well characterised were introduced as candidates for the treatment of Chagas disease. In vitro and in vivo assays were performed in order to test the effectiveness of these compounds. Finally, those which showed the best activity underwent additional studies in order to elucidate the possible mechanism of action. In vitro results indicated that some compounds have low toxicity (i.e. >150 μM, against Vero cell) combined with high efficacy (i.e. <20 μM) against some forms of T. cruzi. Further in vivo studies on mice models confirmed the expectations of improvements in infected mice. In vivo tests on the acute phase gave parasitaemia inhibition values higher those of Bz, and a remarkable decrease in the reactivation of parasitaemia was found in the chronic phase after immunosuppression of the mice treated with one of the compounds. The morphological alterations found in treated parasites with our derivatives confirmed extensive damage; energetic metabolism disturbances were also registered by (1)H NMR. The demonstrated in vivo activity and low toxicity, together with the use of affordable starting products and the lack of synthetic complexity, put these abietic acid derivatives in a remarkable position toward the development of an anti-Chagasic agent.
authors.affiliation: Department of Parasitology, Instituto de Investigación Biosanitaria ibs, University of Granada, Severo Ochoa s/n, E-18071 Granada, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Olmo
authors.affiliation: Department of Organic Chemistry, University of Granada, Severo Ochoa s/n, E-18071 Granada, Spain.
authors.forename: J J
authors.initials: JJ
authors.lastname: Guardia
authors.affiliation: Department of Parasitology, Instituto de Investigación Biosanitaria ibs, University of Granada, Severo Ochoa s/n, E-18071 Granada, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Marin
authors.affiliation: Department of Organic Chemistry, University of Granada, Severo Ochoa s/n, E-18071 Granada, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Messouri
authors.affiliation: Department of Parasitology, Instituto de Investigación Biosanitaria ibs, University of Granada, Severo Ochoa s/n, E-18071 Granada, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Rosales
authors.affiliation: Department of Parasitology, Instituto de Investigación Biosanitaria ibs, University of Granada, Severo Ochoa s/n, E-18071 Granada, Spain.
authors.forename: K
authors.initials: K
authors.lastname: Urbanová
authors.affiliation: Department of Organic Chemistry, University of Granada, Severo Ochoa s/n, E-18071 Granada, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Chayboun
authors.affiliation: Department of Organic Chemistry, University of Granada, Severo Ochoa s/n, E-18071 Granada, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Chahboun
authors.affiliation: Department of Organic Chemistry, University of Granada, Severo Ochoa s/n, E-18071 Granada, Spain.
authors.forename: E J
authors.initials: EJ
authors.lastname: Alvarez-Manzaneda
authors.affiliation: Department of Parasitology, Instituto de Investigación Biosanitaria ibs, University of Granada, Severo Ochoa s/n, E-18071 Granada, Spain. Electronic address: msanchem@ugr.es.
authors.forename: M
authors.initials: M
authors.lastname: Sánchez-Moreno
mesh_terms: D045784:Abietanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects*; D014709:Vero Cells
chemical_list: D045784:Abietanes; D000981:Antiprotozoal Agents; C023710:abietic acid
keywords: Abietic acid; Anti-chagasic; Chemotherapy; Trypanosomiasis