Naftifine-analogues as anti-Trypanosoma cruzi agents

被引：34

作者：

Gerpe, Alejandra ^{[1
]}

Boiani, Lucia ^{[1
]}

Hernandez, Paola ^{[1
]}

Sortino, Maximiliano ^{[2
]}

Zacchino, Susana ^{[2
]}

Gonzalez, Mercedes ^{[1
]}

Cerecetto, Hugo ^{[1
]}

机构：

[1] Univ Republica, Fac Ciencias, Fac Quim, Dept Quim Organ, Montevideo 11400, Uruguay

[2] Univ Nacl Rosario, Catedra Farmacognosia, Fac Ciencias Bioquim & Farmaceut, RA-2000 Rosario, Santa Fe, Argentina

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 45卷 / 06期

关键词：

Alkenylamine; Indazole N-oxide; Benzofuroxan; Benzimidazole 1,3-dioxide; Quinoxaline 1,4-dioxide; Anti-T cruzi agents; ALLYLAMINE ANTIMYCOTIC TERBINAFINE; OXIDOSQUALENE CYCLASE INHIBITORS; CHAGAS-DISEASE CONTROL; BIOLOGICAL EVALUATION; SQUALENE EPOXIDASE; DERIVATIVES; KETOCONAZOLE; TRYPANOSOMA-(SCHIZOTRYPANUM)-CRUZI; EPIMASTIGOTES; CHEMOTHERAPY;

D O I：

10.1016/j.ejmech.2010.01.052

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Chagas disease represents a relevant health problem in Central and South America. The first line of treatment is Nifurtimox and Benznidazole which have a great deal of disadvantages that demands the rapid generation of therapeutic alternatives. Based in our research on aza-thiaheterocycles as anti-Trypanosoma cruzi agents we identified pharmacophores that act through oxidative stress. Here, we describe the synthesis and the activity of new containing bioactive-heterocycles analogues of naftifine as potential T. cruzi membrane sterol biosynthesis inhibitors. Benzimidazole 1,3-dioxides (11 and 13) and quinoxaline 1,4-dioxides (22 and 23) displayed excellent parasite/mammal selectivity indexes. Analysis of the free sterols from parasite incubated with the compounds showed that any of them are able to accumulate squalene suggesting that in the anti-T. cruzi mechanism of action is not involved the inhibition of sterol biosynthesis. Some derivatives were also tested as antifungal agents. The results obtained in the present work open potential therapeutic possibilities of new compounds for these infectious diseases.

引用

页码：2154 / 2164

页数：11

共 49 条

[1]

Quinoxaline NN′-dioxide derivatives and related compounds as growth inhibitors of Trypanosoma cruzi.: Structure-activity YP relationships [J].

Aguirre, G ;

Cerecetto, H ;

Di Maio, R ;

González, M ;

Alfaro, MEM ;

Jaso, A ;

Zarranz, B ;

Ortega, MA ;

Aldana, I ;

Monge-Vega, A .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (14) :3835-3839

[2]

Trypanosoma cruzi:: Characterization of an intracellular epimastigote-like form [J].

Almeida-de-Faria, M ;

Freymüller, E ;

Colli, W ;

Alves, MJM .

EXPERIMENTAL PARASITOLOGY, 1999, 92 (04) :263-274

[3]

Heterocyclic-2-carboxylic Acid (3-Cyano-1,4-di-N-oxidequinoxalin-2-yl)amide Derivatives as Hits for the Development of Neglected Disease Drugs [J].

Ancizu, Saioa ;

Moreno, Elsa ;

Torres, Enrique ;

Burguete, Asuncion ;

Perez-Silanes, Silvia ;

Benitez, Diego ;

Villar, Raquel ;

Solano, Beatriz ;

Marin, Adoracion ;

Aldana, Ignacio ;

Cerecetto, Hugo ;

Gonzalez, Mercedes ;

Monge, Antonio .

MOLECULES, 2009, 14 (06) :2256-2272

[4]

Synthesis and biological properties of new 5-nitroindazole derivatives [J].

Arán, VJ ;

Ochoa, C ;

Boiani, L ;

Buccino, P ;

Cerecetto, H ;

Gerpe, A ;

González, M ;

Montero, D ;

Nogal, JJ ;

Gómez-Barrio, A ;

Azqueta, A ;

de Ceráin, AL ;

Piro, OE ;

Castellano, EE .

BIOORGANIC & MEDICINAL CHEMISTRY, 2005, 13 (09) :3197-3207

[5]

STRUCTURE OF POLYGODIAL - A NEW SESQUITERPENE DIALDEHYDE FROM POLYGONUM HYDROPIPER L [J].

BARNES, CS ;

LODER, JW .

AUSTRALIAN JOURNAL OF CHEMISTRY, 1962, 15 (02) :322-&

[6]

Current treatment approaches to leishmaniasis [J].

Berman, J .

CURRENT OPINION IN INFECTIOUS DISEASES, 2003, 16 (05) :397-401

[7]

2H-benzimidazole 1,3-dioxide derivatives:: A new family of water-soluble anti-trypanosomatid agents [J].

Boiani, Mariana ;

Boiani, Lucia ;

Denicola, Ana ;

Torres de Ortiz, Susana ;

Serna, Elva ;

Vera de Bilbao, Ninfa ;

Sanabria, Luis ;

Yaluff, Gloria ;

Nakayama, Hector ;

Rojas de Arias, Antonieta ;

Vega, Celeste ;

Rolan, Miriam ;

Gomez-Barrio, Alicia ;

Cerecetto, Hugo ;

Gonzalez, Mercedes .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (11) :3215-3224

[8]

Second generation of 2H-benzimidazole 1,3-dioxide derivatives as anti-trypanosomatid agents: Synthesis, biological evaluation, and mode of action studies [J].

Boiani, Mariana ;

Boiani, Lucia ;

Merlino, Alicia ;

Hernandez, Paola ;

Chidichimo, Agustina ;

Cazzulo, Juan J. ;

Cerecetto, Hugo ;

Gonzalez, Mercedes .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2009, 44 (11) :4426-4433

[9]

Potent anti-Trypanosoma cruzi activities of oxidosqualene cyclase inhibitors [J].

Buckner, FS ;

Griffin, JH ;

Wilson, AJ ;

Van Voorhis, WC .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2001, 45 (04) :1210-1215

[10]

Neglected Tropical Diseases: Multi-Target-Directed Ligands in the Search for Novel Lead Candidates against Trypanosoma and Leishmania [J].

Cavalli, Andrea ;

Bolognesi, Maria Laura .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (23) :7339-7359

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