2. Academic Validation
  3. Design and synthesis of a new series of 3,5-disubstituted isoxazoles active against Trypanosoma cruzi and Leishmania amazonensis

Design and synthesis of a new series of 3,5-disubstituted isoxazoles active against Trypanosoma cruzi and Leishmania amazonensis

  • Eur J Med Chem. 2017 Mar 10:128:25-35. doi: 10.1016/j.ejmech.2017.01.029.
Rafael da Rosa 1,  Milene Höehr de Moraes 2,  Lara Almida Zimmermann 1,  Eloir Paulo Schenkel 1,  Mario Steindel 2,  Lílian Sibelle Campos Bernardes 3
Affiliations

Affiliations

  • 1 Pharmaceutical and Medicinal Chemistry Laboratory, Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianópolis, 88040-900 SC, Brazil.
  • 2 Protozoology Laboratory, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, 88040-900 SC, Brazil.
  • 3 Pharmaceutical and Medicinal Chemistry Laboratory, Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianópolis, 88040-900 SC, Brazil. Electronic address: l.bernardes@ufsc.br.
PMID: 28152426 DOI: 10.1016/j.ejmech.2017.01.029
Abstract

Chagas disease and leishmaniasis are neglected tropical diseases (NTDs) endemic in developing countries. Although there are drugs available for their treatment, efforts on finding new efficacious therapies are continuous. The natural Lignans grandisin (1) and veraguensin (2) show activity against trypomastigote T. cruzi and their scaffold has been used as inspiration to design new derivatives with improved potency and chemical properties. We describe here the planning and microwave-irradiated synthesis of 26 isoxazole derivatives based on the structure of the Lignans 1 and 2. In addition, the in vitro evaluation against culture trypomastigotes and intracellular amastigotes of T. cruzi and intracellular amastigotes of L. amazonensis and L. infantum is reported. Among the synthesized derivatives, compounds 17 (IC50 = 5.26 μM for T. cruzi), 29 (IC50 = 1.74 μM for T. cruzi) and 31 (IC50 = 1.13 μM for T. cruzi and IC50 = 5.08 μM for L. amazonensis) were the most active and were also evaluated against recombinant trypanothione reductase of T. cruzi in a preliminary study of their mechanism of action.

Keywords

Drug design; Isoxazole; Leishmania amazonensis; Natural product analogues; Trypanosoma cruzi; Trypanothione reductase.

Figures