Dimeric Flavonoids from Arrabidaea brachypoda and Assessment of Their Anti-Trypanosoma cruzi Activity Cla ́ udia Quintino da Rocha, † Emerson Ferreira Queiroz, ‡ Ca ́ ssio Santana Meira, § Diogo Rodrigo Magalha ̃ es Moreira, § Milena Botelho Pereira Soares, § Laurence Marcourt, ‡ Wagner Vilegas,* ,† and Jean-Luc Wolfender* ,‡ † Laborató rio de Biodiversidade e Sustentabilidade, UNESP  Universidade Estadual Paulista, Coastal Campus, Parque Bitaru, CEP 11330-900, Sã o Vicente, Brazil ‡ School of Pharmaceutical Sciences, Phytochemistry and Bioactive Natural Products, University of Geneva, University of Lausanne, CH-1211 Geneva 4, Switzerland § Centro de Pesquisas Gonç alo Moniz, Fundaç ã o Oswaldo Cruz (Fiocruz), Candeal, CEP 40296-710, Salvador, Brazil * S Supporting Information ABSTRACT: The nonpolar fraction of an aqueous ethanol extract of the roots of Arrabidaea brachypoda, a Brazilian medicinal plant, demonstrated significant in vitro activity against Trypanosoma cruzi, the parasite responsible for Chagas disease. Targeted isolation of the active constituents led to the isolation of three new dimeric flavonoids (1-3), and their structures were elucidated using UV, NMR, and HRMS analysis, as well as by chemical derivatization. The anti-T. cruzi activity and cytotoxicity toward mammalian cells were determined for these substances. Compound 1 exhibited no activity toward T. cruzi, while flavonoids 2 and 3 exhibited selective activity against these trypomastigotes. Compounds 2 and 3 inhibited the parasite invasion process and its intracellular development in host cells with similar potencies to benznidazole. In addition, compound 2 reduced the blood parasitemia of T. cruzi-infected mice. This study has revealed that these two dimeric flavonoids represent potential anti-T. cruzi lead compounds for further drug development. T he family Bignoniaceae encompasses 120 genera and approximately 800 species of plants that are distributed mostly in tropical and subtropical regions. 1 The genus Arrabidaea belongs to the tribe Bignonieae and contains approximately 70 species that occur from Mexico to Argentina. This genus is a large and morphologically diverse clade of Neotropical lianas. 2 Previous phytochemical studies have shown plants in this genus to produce C-glucosylxanthones, phenyl- propanoids, flavonoids (inclusive of anthocyanidins), allantoin derivatives, and triterpenes. 1,3,4 In traditional medicine, species from the genus Arrabidaea are used for different therapeutic purposes and have astringent, anti-inflammatory, antimicrobial, and antitumor properties. 1,4,5 In Brazil, Arrabidaea brachypoda Bureau is commonly known as “cervejinha do campo” and is native to the “cerrado” ecosystem. Its traditional uses include the treatment of kidney stones and painful joints (arthritis), while it has also demonstrated significant in vivo anti-inflammatory activity in animal models. 6 Chagas disease is a parasitic disease caused by the flagellate protozoan Trypanosoma cruzi. This disease is transmitted to humans mainly in rural endemic areas through the infected feces of triatomine insects. However, when infected people from rural regions began to migrate to cities, the disease then spread to different, nonendemic areas. 7 The World Health Organization (WHO) reports that globally approximately 10 million people are infected by T. cruzi, and more than 25 million people are at risk of infection in endemic countries. 8 Due to population migration, this disease also affects northern countries. In 2007, more than 100 000 T. cruzi-infected patients were living in the United States. 9 Chagas disease is treated mainly using benznidazole, even though this compound demonstrates limited effectiveness and severe side effects. 10 As more effective drugs are required, efforts have been devoted to discovering new lead compounds from natural products to combat T. cruzi infections. 11,12 The Biota/FAPESP research program for the sustainable use of Brazilian biodiversity (www.biota.org.br) includes the search for new lead compounds for treating Chagas disease within its research program. Consequently, different plants were screened for their antiparasitic activities, and A. brachypoda exhibited promising in vitro and in vivo anti-T. cruzi activities. This study describes Received: January 22, 2014 Published: May 28, 2014 Article pubs.acs.org/jnp © 2014 American Chemical Society and American Society of Pharmacognosy 1345 dx.doi.org/10.1021/np401060j | J. Nat. Prod. 2014, 77, 1345-1350