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New 1,2,3‐triazole‐based analogues of benznidazole for use against Trypanosoma cruzi infection: In vitro and in vivo evaluations
Author(s) -
Leite Débora Inácio,
Fontes Fábio de Vasconcellos,
Bastos Monica Macedo,
Hoelz Lucas Villas Boas,
Bianco Maria da Conceição Avelino Dias,
de Oliveira Andressa Paula,
da Silva Patricia Bernardino,
da Silva Cristiane França,
Batista Denise da Gama Jean,
da Gama Aline Nefertiti Silva,
Peres Raiza Brandão,
Villar Jose Daniel Figueroa,
Soeiro Maria de Nazaré Correia,
Boechat Nubia
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13333
Subject(s) - benznidazole , trypanosoma cruzi , trypanocidal agent , bioisostere , in vivo , chagas disease , amastigote , in vitro , pharmacology , nifurtimox , triazole , chemistry , biology , biochemistry , chemical synthesis , virology , microbiology and biotechnology , leishmania , organic chemistry , parasite hosting , world wide web , computer science
Chagas disease has spread throughout the world mainly because of the migration of infected individuals. In Brazil, only benznidazole (Bnz) is used; however, it is toxic and not active in the chronic phase, and cases of resistance are described. This work aimed at the synthesis and the trypanocidal evaluation in vitro and in vivo of six new Bnz analogues ( 3–8 ). They were designed by exploring the bioisosteric substitution between the amide group contained in Bnz and the 1,2,3‐triazole ring. All the compounds were synthesized in good yields. With the exception of compound 7 , the in vitro biological evaluation shows that all Bnz analogues were active against the amastigote form, whereas only compounds 3 , 4 , 5 , and 8 were active against trypomastigote. Compounds 4 and 5 showed the most promising activities in vitro against the form of trypomastigote, being more active than Bnz. In vivo evaluation of compounds, 3–8 showed lower potency and higher toxicity than Bnz. Although the 1,2,3‐triazole ring has been described in the literature as an amide bioisostere, its substitution here has reduced the activity of the compounds and made them more toxic. Thus, further molecular optimization could provide novel therapeutic agents for Chagas’ disease.