title: Design, synthesis, and evaluation of hydroxamic acid derivatives as promising agents for the management of Chagas disease.
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 (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.
authors.affiliation: Laboratório de Síntese Orgânica, Departamento de Química, Instituto Militar de Engenharia, IME , Rio de Janeiro, Brasil.
authors.forename: Giseli Capaci
authors.initials: GC
authors.lastname: Rodrigues
authors.forename: Daniel Ferreira
authors.initials: DF
authors.lastname: Feijó
authors.forename: Marcelo Torres
authors.initials: MT
authors.lastname: Bozza
authors.forename: Peiwen
authors.initials: P
authors.lastname: Pan
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Seppo
authors.initials: S
authors.lastname: Parkkila
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Clemente
authors.initials: C
authors.lastname: Capasso
authors.forename: Alcino Palermo
authors.initials: AP
authors.lastname: Aguiar
authors.forename: Alane Beatriz
authors.initials: AB
authors.lastname: Vermelho
mesh_terms: D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000378:metabolism; D045744:Cell Line, Tumor; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D015195:Drug Design; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D010447:Peptide Hydrolases / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D006877:Hydroxamic Acids; D007527:Isoenzymes; D007555:Isoxazoles; D011480:Protease Inhibitors; D014344:Trypanocidal Agents; D010447:Peptide Hydrolases; D002256:Carbonic Anhydrases