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

作者：da Rosa Rafael; de Moraes Milene Hoeehr; Zimmermann Lara Almida; Schenkel Eloir Paulo; Steindel Mario; Campos Bernardes Lilian Sibelle

来源：European Journal of Medicinal Chemistry, 2017, 128: 25-35.

DOI：10.1016/j.ejmech.2017.01.029

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

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 mu M for T. cruzi), 29 (IC50 = 1.74 mu M for T. cruzi) and 31 (IC50 = 1.13 mu M for T. cruzi and IC50 = 5.08 mu M 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.

• 出版日期2017-3-10