Hydroxamic acid derivatives: a promising scaffold for rational compound optimization in Chagas disease.

Abstract

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.

• Authors: Dayanne da Rocha de Menezes, Claudia Magalhães Calvet, Giseli Capaci Rodrigues, Mirian Claudia de Souza Pereira, Igor Rodrigues Almeida, Alcino Palermo de Aguiar, Claudiu T Supuran, Alane Beatriz Vermelho
• Journal: Journal of enzyme inhibition and medicinal chemistry (J Enzyme Inhib Med Chem) Vol. 31 Issue 6 Pg. 964-73 (Dec 2016) ISSN: 1475-6374 [Electronic] England
• PMID: 26327246 (Publication Type: Journal Article)

Chemical References

• Hydroxamic Acids
• Trypanocidal Agents

Topics

• Animals
• Cells, Cultured
• Chagas Disease (drug therapy, microbiology)
• Dose-Response Relationship, Drug
• Hydroxamic Acids (chemical synthesis, chemistry, pharmacology)
• Macrophages (drug effects, microbiology)
• Mice
• Molecular Structure
• Myocytes, Cardiac (drug effects, microbiology)
• Structure-Activity Relationship
• Trypanocidal Agents (chemical synthesis, chemistry, pharmacology)
• Trypanosoma cruzi (drug effects)