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

被引：48
作者：
da Rosa, Rafael [1 ]
de Moraes, Milene Hoeehr [2 ]
Zimmermann, Lara Almida [1 ]
Schenkel, Eloir Paulo [1 ]
Steindel, Mario [2 ]
Campos Bernardes, Lilian Sibelle [1 ]
机构：
[1] Univ Fed Santa Catarina, Dept Pharmaceut Sci, Pharmaceut & Med Chem Lab, BR-88040900 Florianopolis, SC, Brazil
[2] Univ Fed Santa Catarina, Dept Microbiol Immunol & Parasitol, Protozool Lab, BR-88040900 Florianopolis, SC, Brazil
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 128卷
关键词：
Natural product analogues; Drug design; Isoxazole; Trypanosoma cruzi; Leishmania amazonensis; Trypanothione reductase; TRYPANOTHIONE REDUCTASE INHIBITORS; ASSISTED ORGANIC-SYNTHESIS; IN-VITRO ACTIVITY; NATURAL-PRODUCTS; DRUG DISCOVERY; TETRAHYDROFURAN LIGNANS; BIOLOGICAL EVALUATION; TRYPANOCIDAL ACTIVITY; GLYCOSIDES; STRATEGIES;
D O I：
10.1016/j.ejmech.2017.01.029
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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. (C) 2017 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码：25 / 35
页数：11
相关论文
共 75 条
[1]   The mucin-like glycoprotein super-family of Trypanosoma cruzi:: structure and biological roles [J].
Acosta-Serrano, A ;
Almeida, IC ;
Freitas, LH ;
Yoshida, N ;
Schenkman, S .
MOLECULAR AND BIOCHEMICAL PARASITOLOGY, 2001, 114 (02) :143-150
[2]  
AHMED R, 1976, TETRAHEDRON, V32, P1339, DOI 10.1016/0040-4020(76)85006-5
[3]   Synthesis, cytotoxicity, and anti-Trypanosoma cruzi activity of new chalcones [J].
Aponte, Jose C. ;
Verastegui, Manuela ;
Malaga, Edith ;
Zimic, Mirko ;
Quiliano, Miguel ;
Vaisberg, Abraham J. ;
Gilman, Robert H. ;
Hammond, Gerald B. .
JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (19) :6230-6234
[4]  
Armarego WLF, 2009, PURIFICATION OF LABORATORY CHEMICALS, 6TH EDITION, P88, DOI 10.1016/B978-1-85617-567-8.50012-3
[5]   Efficient technique for screening drugs for activity against Trypanosoma cruzi using parasites expressing beta-galactosidase [J].
Buckner, FS ;
Verlinde, CLMJ ;
LaFlamme, AC ;
vanVoorhis, WC .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1996, 40 (11) :2592-2597
[6]   Neolignans from plants in northeastern Brazil (Lauraceae) with activity against Trypanosoma cruzi [J].
Cabral, M. M. O. ;
Barbosa-Filho, J. M. ;
Maia, G. L. A. ;
Chaves, M. C. O. ;
Braga, M. V. ;
De Souza, W. ;
Soares, R. O. A. .
EXPERIMENTAL PARASITOLOGY, 2010, 124 (03) :319-324
[7]   Synthesis and trypanocidal activity of 1,4-bis-(3,4,5-trimethoxy-phenyl)-1,4-butanediol and 1,4-bis-(3,4-dimethoxyphenyl)-1,4-butanediol [J].
Campos Bernardes, Lilian Sibelle ;
Kato, Massuo Jorge ;
Albuquerque, Sergio ;
Carvalho, Ivone .
BIOORGANIC & MEDICINAL CHEMISTRY, 2006, 14 (21) :7075-7082
[8]   Design and synthesis of new (E)-cinnamic N-acylhydrazones as potent antitrypanosomal agents [J].
Carvalho, Samir A. ;
Feitosa, Larisse O. ;
Soares, Marcio ;
Costa, Thadeu E. M. M. ;
Henriques, Maria G. ;
Salomao, Kelly ;
de Castro, Solange L. ;
Kaiser, Marcel ;
Brun, Reto ;
Wardell, James L. ;
Wardell, Solange M. S. V. ;
Trossini, Gustavo H. G. ;
Andricopulo, Adriano D. ;
da Silva, Edson F. ;
Fraga, Carlos A. M. .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2012, 54 :512-521
[9]   Complementary medicinal chemistry-driven strategies toward new antitrypanosomal and antileishmanial lead drug candidates [J].
Cavalli, Andrea ;
Lizzi, Federica ;
Bongarzone, Salvatore ;
Belluti, Federica ;
Piazzi, Lorna ;
Bolognesi, Maria Laura .
FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY, 2010, 58 (01) :51-60
[10]   Design, synthesis, and biological evaluation of crenatoside analogues as novel influenza neuraminidase inhibitors [J].
Chen, Bao-Long ;
Wang, Ya-Jing ;
Guo, Hong ;
Zeng, Guang-Yao .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2016, 109 :199-205
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