Design, Synthesis, and Evaluation of Hydroxamic Acid Derivatives as Promising Agents for the Management of Chagas Disease Giseli Capaci Rodrigues, †,‡,§ Daniel Ferreira Feijó , ∥ Marcelo Torres Bozza, ∥ Peiwen Pan, ⊥ Daniela Vullo, # Seppo Parkkila, ⊥ Claudiu T. Supuran, #,∇ Clemente Capasso, ○ Alcino Palermo Aguiar, † and Alane Beatriz Vermelho* ,‡,◆ † Laborató rio de Síntese Orgâ nica, Departamento de Química, Instituto Militar de Engenharia, IME, Rio de Janeiro, Brasil ‡ Laborató rio Proteases de Microrganismos, Departamento de Microbiologia, Instituto de Microbiologia Paulo de Gó es, IMPG, Universidade Federal do Rio de Janeiro, UFRJ, Rio de Janeiro, Brasil § Escola de Ciê ncia e Tecnologia e Programa de Pó s-Graduaç ã o em Ensino das Ciê ncias, Universidade do Grande Rio, Unigranrio, Duque de Caxias, Rio de Janeiro, Brasil ∥ Laborató rio de Inflamaç ã o e Imunidade, Departamento de Imunologia, Instituto de Microbiologia Paulo de Gó es, IMPPG, Universidade Federal do Rio de Janeiro, UFRJ, Rio de Janeiro, Brasil ⊥ Institute of Biomedical Technology, Fimlab Ltd., School of Medicine and BioMediTech, University of Tampere and Tampere University Hospital, Medisiinarinkatu 3, 33520 Tampere, Finland # Laboratorio di Chimica Bioinorganica, Universita degli Studi di Firenze, Via della Lastruccia 3, Rm. 188, Polo Scientifico, 50019 Sesto Fiorentino, Florence, Italy ∇ Dipartimento NEIROFARBA, Sezione di Scienze Farmaceutiche, Universita degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy ○ Istituto di Biochimica delle Proteine, CNR, Via P. Castellino 111, 80131 Napoli, Italy ◆ Biotecnologia − BIOINOVAR: Unidade de Bioenergia, Biocatalise e Bioprodutos, Instituto de Microbiologia Paulo de Gó es, IMPG, Universidade Federal do Rio de Janeiro, UFRJ, Rio de Janeiro, Brasil ABSTRACT: Today, there are approximately 8 million cases of Chagas disease in the southern cone of South America alone, and about 100 million people are living with the risk of becoming infected. The present pharmacotherapy is sometimes ineffective and has serious side effects. Here, we report a series of 4,5- dihydroisoxazoles incorporating hydroxamate moieties, which act as effective inhibitors of the carbonic anhydrase (CA) from Trypanosoma cruzi (TcCA). One compound (5g) was evaluated in detail and shows promising features as an antitrypanosomal agent. Excellent values for the inhibition of growth for all three developmental forms of the parasite were observed at low concentrations of 5g (IC 50 values from 7.0 to <1 μM). The compound has a selectivity index (SI) of 6.7 and no cytotoxicity to macrophage cells. Preliminary in vivo data showed that 5g reduces bloodstream parasites and that all treated mice survived; it was also more effective than the standard drug benznidazole. ■ INTRODUCTION American trypanosomiasis, or Chagas disease, is caused by the parasite Trypanosoma cruzi. This infection was initially described in 1909 by the Brazilian physician Carlos Chagas (1879−1934). About 8 million people worldwide are estimated to be infected by T. cruzi. 1 Furthermore, because of growing population migration, the disease has spread to other continents. 2,3 Chagas disease is transmitted to humans by the infected feces of blood-sucking triatomine bugs (Figure 1), a vector for the T. cruzi parasite; however, other routes of transmission are known, such as consumption of contaminated food and drink, congenital, and blood transfusions. 1,4−8 The pathogenesis of the disease can be divided into three phases: (i) a short acute phase, (ii) a long-lasting latent phase, and (iii) a chronic phase, which emerges in about 30% of the patients. Serious chronic symptoms such as cardiomyopathy and malformations of the intestines (e.g., megaesophagus and megacolon) have been reported. Chagas disease chemotherapy is limited to nifurtimox and benznidazole; both drugs were developed more than 30 years ago. They are predominantly active during the acute phase of the disease. However, they have serious adverse effects because of their high toxicity and a low efficacy, especially in the chronic phase. 9 The lack of efficient treatments and acquired resistance to the existing treatments has stimulated efforts to identify new, Received: June 17, 2013 Published: December 3, 2013 Featured Article pubs.acs.org/jmc © 2013 American Chemical Society 298 dx.doi.org/10.1021/jm400902y | J. Med. Chem. 2014, 57, 298−308