Differential lethal action of C17:2 and C17:0 anacardic acid derivatives in Trypanosoma cruzi – A mechanistic study

• Published in: Bioorganic chemistry Vol. 102; p. 104068
• Main Authors: Umehara, Eric, Costa Silva, Thais A., Mendes, Viviane M., Guadagnin, Rafael C., Sartorelli, Patricia, Tempone, Andre G., Lago, João Henrique G.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.09.2020; Elsevier
• Subjects: Anacardic acid derivatives; Anacardic Acids - pharmacology; Anacardic Acids - therapeutic use; Animals; Biochemistry & Molecular Biology; Chagas Disease - drug therapy; Chemistry; Chemistry, Organic; Female; Life Sciences & Biomedicine; Male; Mice; Mitochondrial membrane potential; Physical Sciences; Plant Leaves - chemistry; Plasma membrane; Schinus terebinthifolius; Science & Technology; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; Schinus terebinthifolius; Anacardic acid derivatives; Plasma membrane; Trypanosoma cruzi; Mitochondrial membrane potential; MITOCHONDRIA; CHAGAS-DISEASE; TARGETS
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104068

[Display omitted] •A C17:2 derivative of anacardic acid (1) was isolated from Schinus terebinthifolius.•Compound 1 was subjected to hydrogenation to afford a C17:0 derivative (1a).•Compounds 1 and 1a displayed activity against Trypanosoma cruzi.•Compound 1 significantly altered cell membrane permeability.•Compound 1a induced alteration in the mitochondrial membrane. The n-hexane extract from leaves of Schinus terebinthifolius (Anacardiaceae) induced 100% of death of trypomastigote forms of T. cruzi at 300 μg/mL and was subjected to a bioactivity-guided fractionation to afford a C17:2 derivative of anacardic acid [6-(8′Z,11′Z)-heptadecadienyl-salicylic acid, 1]. Additionally, compound 1 was subjected to hydrogenation procedures to afford a C17:0 derivative (6-heptadecanyl-salicylic acid, 1a). Compounds 1 and 1a were effective in killing trypomastigote forms of T. cruzi with IC50 values of 8.3 and 9.0 μM, respectively, while a related compound, salicylic acid, was inactive. Furthermore, no cytotoxicity was observed for the highest tested concentration (CC50 > 200 µM) for all evaluated compounds. Due to the promising results, the mechanism of parasite death was investigated for compounds 1 and 1a using flow cytometry and spectrofluorimetry. The cell membrane permeability assay with SYTOX Green indicated that compound 1 significantly altered this parameter after 40 min of incubation, while compound 1a caused no alteration. Considering that the hydrogenation rendered a differential cellular target in parasites, additional assays were performed with 1a. Despite no permeabilization of the plasma membrane, compound 1a induced depolarization of the electric potential after two hours of incubation. The mitochondria of the parasite were also affected by compound 1a, with depolarization of the mitochondrial membrane potential, and reduction of reactive oxygen species (ROS) levels. The Ca2+ levels were not affected during the time of incubation. Considering that the mitochondrion is a single organelle in Trypanosoma cruzi for ATP generation, compounds affecting the bioenergetic system are of interest for drug discovery against Trypanosomatids.