Design and synthesis of a new series of 3,5-disubstituted isoxazoles active against Trypanosoma cruzi and Leishmania amazonensis.
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.
Pharmaceutical and Medicinal Chemistry Laboratory, Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianópolis, 88040-900 SC, Brazil.
Rafael
R
da Rosa
Protozoology Laboratory, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, 88040-900 SC, Brazil.
Milene Höehr
MH
de Moraes
Pharmaceutical and Medicinal Chemistry Laboratory, Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianópolis, 88040-900 SC, Brazil.
Lara Almida
LA
Zimmermann
Pharmaceutical and Medicinal Chemistry Laboratory, Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianópolis, 88040-900 SC, Brazil.
Eloir Paulo
EP
Schenkel
Protozoology Laboratory, Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, 88040-900 SC, Brazil.
Mario
M
Steindel
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.
Lílian Sibelle Campos
LSC
Bernardes
D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D005663:Furans / Q000494:pharmacology; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology; D018314:Leishmania infantum / Q000187:drug effects* / Q000254:growth & development; D007894:Leishmania mexicana / Q000187:drug effects* / Q000254:growth & development; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology; D017705:Lignans / Q000494:pharmacology; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development
D000981:Antiprotozoal Agents; D005663:Furans; D007555:Isoxazoles; D017705:Lignans; C084077:galgravin; C074346:grandisin; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase
Drug design; Isoxazole; Leishmania amazonensis; Natural product analogues; Trypanosoma cruzi; Trypanothione reductase