title: Antiparasitic evaluation of betulinic acid derivatives reveals effective and selective anti-Trypanosoma cruzi inhibitors.
abstract: Betulinic acid is a pentacyclic triterpenoid with several biological properties already described, including antiparasitic activity. Here, the anti-Trypanosoma cruzi activity of betulinic acid and its semi-synthetic amide derivatives (BA1-BA8) was investigated. The anti-Trypanosoma cruzi activity and selectivity were enhanced in semi-synthetic derivatives, specially on derivatives BA5, BA6 and BA8. To understand the mechanism of action underlying betulinic acid anti-T. cruzi activity, we investigated ultrastructural changes by electron microscopy. Ultrastructural studies showed that trypomastigotes incubated with BA5 had membrane blebling, flagella retraction, atypical cytoplasmic vacuoles and Golgi cisternae dilatation. Flow cytometry analysis showed that parasite death is mainly caused by necrosis. Treatment with derivatives BA5, BA6 or BA8 reduced the invasion process, as well as intracellular parasite development in host cells, with a potency and selectivity similar to that observed in benznidazole-treated cells. More importantly, the combination of BA5 and benznidazole revealed synergistic effects on trypomastigote and amastigote forms of T. cruzi. In conclusion, we demonstrated that BA5 compound is an effective and selective anti-T. cruzi agent.
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, BA, Brazil.
authors.forename: Cássio Santana
authors.initials: CS
authors.lastname: Meira
authors.affiliation: Laboratório de Tecnologia Farmacêutica, Universidade Federal da Paraíba, João Pessoa, PB, Brazil.
authors.forename: José Maria
authors.initials: JM
authors.lastname: Barbosa-Filho
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, BA, Brazil.
authors.forename: Adriana
authors.initials: A
authors.lastname: Lanfredi-Rangel
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, BA, Brazil; Universidade do Estado da Bahia, Departamento de Ciências da Vida, Salvador, BA, Brazil.
authors.forename: Elisalva Teixeira
authors.initials: ET
authors.lastname: Guimarães
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, BA, Brazil.
authors.forename: Diogo Rodrigo Magalhães
authors.initials: DR
authors.lastname: Moreira
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, BA, Brazil; Hospital São Rafael, Centro de Biotecnologia e Terapia Celular, Salvador, BA, Brazil. Electronic address: milena@bahia.fiocruz.br.
authors.forename: Milena Botelho Pereira
authors.initials: MB
authors.lastname: Soares
mesh_terms: D000818:Animals; D017304:Annexin A5; D004396:Coloring Agents; D004357:Drug Synergism; D005434:Flow Cytometry; D020128:Inhibitory Concentration 50; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D009593:Nitroimidazoles / Q000494:pharmacology; D053978:Pentacyclic Triterpenes; D011419:Propidium; D013194:Staining and Labeling; D014315:Triterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000648:ultrastructure; D031957:Ziziphus / Q000737:chemistry; D000094062:Betulinic Acid
chemical_list: D017304:Annexin A5; D004396:Coloring Agents; D009593:Nitroimidazoles; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D014344:Trypanocidal Agents; D011419:Propidium; C009999:benzonidazole; D000094062:Betulinic Acid
keywords: Betulinic acid; Chagas disease; Natural compounds; Semi-synthetic; Triterpenoids; Trypanosoma cruzi