Design, Synthesis, and Evaluation of Hydroxamic Acid Derivatives as Promising Agents for the Management of Chagas Disease

• Published in: Journal of medicinal chemistry Vol. 57; no. 2; pp. 298 - 308
• Main Authors: Rodrigues, Giseli Capaci, Feijó, Daniel Ferreira, Bozza, Marcelo Torres, Pan, Peiwen, Vullo, Daniela, Parkkila, Seppo, Supuran, Claudiu T., Capasso, Clemente, Aguiar, Alcino Palermo, Vermelho, Alane Beatriz
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.01.2014; Amer Chemical Soc
• Subjects: Animals; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrases - metabolism; Cell Line, Tumor; Chagas Disease - drug therapy; Chagas Disease - parasitology; Chemistry, Medicinal; Drug Design; Humans; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - pharmacology; Life Sciences & Biomedicine; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - parasitology; Mice; Mice, Inbred BALB C; Peptide Hydrolases - metabolism; Pharmacology & Pharmacy; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Science & Technology; Structure-Activity Relationship; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - enzymology; Trypanosoma cruzi - growth & development; AMERICAN TRYPANOSOMIASIS; CARBONIC-ANHYDRASE; ORAL-TRANSMISSION; PHASE; INHIBITION; ASSAY; TRYPANOSOMA-CRUZI; CYSTEINE PROTEINASE; EXPRESSION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm400902y

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 (IC50 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.