Hydroxamic acid derivatives: a promising scaffold for rational compound optimization in Chagas disease.
This work describes the antitrypanocidal activity of two hydroxamic acid derivatives containing o-ethoxy (HAD1) and p-ethoxy (HAD2) as substituent in the aromatic ring linked to the isoxazoline ring. HAD1 and HAD2 induced a significant reduction in the number of intracellular parasites and consequently showed activity on the multiplication of the parasite. Treatment of cardiomyocytes and macrophages with the compounds revealed no significant loss in cell viability. Ultrastructural alterations after treatment of cardiomyocytes or macrophages infected by Trypanosoma cruzi with the IC50 value of HAD1 revealed alterations to amastigotes, showing initial damage seen as swelling of the kinetoplast. This gave a good indication of the ability of the drug to permeate through the host cell membrane as well as its selectivity to the parasite target. Both compounds HAD1 and 2 were able to reduce the cysteine peptidases and decrease the activity of metallopeptidases.
a BIOINOVAR - Biotechnology Laboratories: Biocatalysis, Bioproducts and Bioenergy, Institute of Microbiology Paulo de Góes, Federal University of Rio de Janeiro , Rio de Janeiro , Brazil .|b Faculdade São Francisco de Barreiras (FASB) , Barreiras , BA , Brazil .
Dayanne da Rocha
Dda R
de Menezes
c Laboratório de Ultra-estrutura Celular, Instituto Oswaldo Cruz - Fiocruz , Rio de Janeiro , RJ , Brazil .
Claudia Magalhães
CM
Calvet
d Escola de Ciência e Tecnologia e Programa de Pós-Graduação em Ensino das Ciências, Universidade do Grande Rio , Duque de Caxias , RJ , Brazil .
Giseli Capaci
GC
Rodrigues
c Laboratório de Ultra-estrutura Celular, Instituto Oswaldo Cruz - Fiocruz , Rio de Janeiro , RJ , Brazil .
Mirian Claudia
MC
de Souza Pereira
e Departamento de Produtos Naturais e Alimentos , Faculdade de Farmácia, UFRJ , Rio de Janeiro , RJ , Brazil .
Igor Rodrigues
IR
Almeida
f Laboratório de Síntese Orgânica, Departamento de Química , Instituto Militar de Engenharia , Rio de Janeiro , Brazil , and.
Alcino Palermo
AP
de Aguiar
g Laboratorio di Chimica Bioinorganica , Università degli Studi di Firenze, Polo Scientifico , Sesto Fiorentino (Florence) , Italy.
Claudiu T
CT
Supuran
a BIOINOVAR - Biotechnology Laboratories: Biocatalysis, Bioproducts and Bioenergy, Institute of Microbiology Paulo de Góes, Federal University of Rio de Janeiro , Rio de Janeiro , Brazil .
Alane Beatriz
AB
Vermelho
D000818:Animals; D002478:Cells, Cultured; D014355:Chagas Disease / Q000188:drug therapy* / Q000382:microbiology; D004305:Dose-Response Relationship, Drug; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000382:microbiology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
D006877:Hydroxamic Acids; D014344:Trypanocidal Agents
Chagas disease; Trypanosoma cruzi; hydroxamic acid derivatives