Londero, Vinicius S.
Costa-Silva, Thais A.
Tempone, Andre G.
Namiyama, Gislene M.
Antar, Guilherme M.
Baitello, Joao B.
Lago, Joao Henrique G.
Total Authors: 8
 Univ Fed Sao Paulo, Inst Ciencias Ambientais Quim & Farmaceut, BR-09972270 Sao Paulo - Brazil
 Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210180 Sao Paulo - Brazil
 Adolfo Lutz Inst, Ctr Parasitol & Micol, BR-01246902 Sao Paulo - Brazil
 Adolfo Lutz Inst, Lab Microscopia Eletron, BR-01246000 Sao Paulo - Brazil
 Univ Sao Paulo, Inst Biociencias, Dept Bot, BR-05508090 Sao Paulo - Brazil
 Inst Florestal, Div Dason, BR-02377000 Sao Paulo - Brazil
Total Affiliations: 6
Web of Science Citations:
As part of our continuous studies on prospecting metabolites from Brazilian plant species with pharmacologic activity against Trypanosoma cruzi, the n-hexane extract from twigs of Nectandra barbellata (Lauraceae) was subjected to a bioactivity-guided fractionation to afford the sesquiterpene costic acid. As results, costic acid induced a trypanocidal effect with IC50 of 37.8 and 7.9 mu M to trypomastigotes and intracellular amastigotes, respectively. When tested in L929 cells, no cytotoxicity was detected in the highest tested concentration (CC50 > 200 mu M), resulting in SI values >5 and >25 to trypomastigotes and amastigotes, respectively. Based on these promising results against T. cruzi, a mechanistic study of the parasite death was investigated. The flow cytometry analysis of costic acid-treated parasites showed depolarization of the plasma membrane electric potential. Spectrofluorimetrical analysis and transmission electron microscopy showed no evidence of plasma membrane permeability alteration of trypomastigotes, but strong ultrastructural damage, evidenced by large vacuoles. Although Ca2+ and reactive oxygen species (ROS) levels were unaltered after short time incubation with costic acid, it rapidly affected the mitochondria, leading to a depolarized potential of the membrane, reducing the ATP levels. In silico studies of costic acid showed good predictions for drug-likeness, with adherence to Lipinskis rules of five (RO5), good ADMET properties and no alerts for Pan-Assay Interference Compounds (PAINS). Therefore, costic acid demonstrated promising activity against T. cruzi parasites, with high selectivity to intracellular amastigotes. Considering the lethal action of costic acid in affecting a vital and unique organelle as the mitochondria, it could be considered a new hit compound for future drug design studies for Chagas disease. (AU)