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

页码：25 / 35

页数：11

共 75 条

[21] Lead Optimization Studies on FimH Antagonists: Discovery of Potent and Orally Bioavailable Ortho-Substituted Biphenyl Mannosides [J].

Han, Zhenfu ;

Pinkner, Jerome S. ;

Ford, Bradley ;

Chorell, Erik ;

Crowley, Jan M. ;

Cusumano, Corinne K. ;

Campbell, Scott ;

Henderson, Jeffrey P. ;

Hultgren, Scott J. ;

Janetka, James W. .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (08) :3945-3959

[22] Natural Product Derived Antiprotozoal Agents: Synthesis, Biological Evaluation, and Structure-Activity Relationships of Novel Chromene and Chromane Derivatives [J].

Harel, Dipak ;

Schepmann, Dirk ;

Prinz, Helge ;

Brun, Reto ;

Schmidt, Thomas J. ;

Wuensch, Bernhard .

JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (18) :7442-7448

[23] The re-emergence of natural products for drug discovery in the genomics era [J].

Harvey, Alan L. ;

Edrada-Ebel, RuAngelie ;

Quinn, Ronald J. .

NATURE REVIEWS DRUG DISCOVERY, 2015, 14 (02) :111-129

[24] Copper(I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates [J].

Himo, F ;

Lovell, T ;

Hilgraf, R ;

Rostovtsev, VV ;

Noodleman, L ;

Sharpless, KB ;

Fokin, VV .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2005, 127 (01) :210-216

[25]

Hotez PJ, 2014, PLOS NEGL TROP DIS, V8

[26] Natural products and Chagas' disease: a review of plant compounds studied for activity against Trypanosoma cruzi [J].

Izumi, Erika ;

Ueda-Nakamura, Tania ;

Dias Filho, Benedito Prado ;

Veiga Junior, Valdir Florencio ;

Nakamura, Celso Vataru .

NATURAL PRODUCT REPORTS, 2011, 28 (04) :809-823

[27] The impact of microwave synthesis on drug discovery [J].

Kappe, CO ;

Dallinger, D .

NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (01) :51-63

[28] Hit and lead criteria in drug discovery for infectious diseases of the developing world [J].

Katsuno, Kei ;

Burrows, Jeremy N. ;

Duncan, Ken ;

van Huijsduijnen, Rob Hooft ;

Kaneko, Takushi ;

Kita, Kiyoshi ;

Mowbray, Charles E. ;

Schmatz, Dennis ;

Warner, Peter ;

Slingsby, B. T. .

NATURE REVIEWS DRUG DISCOVERY, 2015, 14 (11) :751-758

[29] New World and Old World Leishmania Infections: A Practical Review [J].

Kevric, Ines ;

Cappel, Mark A. ;

Keeling, James H. .

DERMATOLOGIC CLINICS, 2015, 33 (03) :579-+

[30]

Khan MOF, 2007, DRUG TARGET INSIGHT, V2, P129

← 1 2 3 4 5 6 7 8 →