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Synthesis of analogues of benznidazole per "click chemistry" and evaluation of antiparasitic activity

Grant number: 10/12245-0
Support type:Scholarships in Brazil - Master
Effective date (Start): March 01, 2011
Effective date (End): May 31, 2012
Field of knowledge:Health Sciences - Pharmacy
Principal researcher:Ivone Carvalho
Grantee:Oswaldo Aparecido Galo
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Chagas disease or South American trypanosomiasis is a disease endemic in Latin America and ranked as the third largest in the tropical parasitic disease after malaria and schistosomiasis. Since the discovery of the disease until today, there were numerous attempts to obtain treatment without effective chemotherapy. The current treatment has been accomplished with the use of nitro-heterocyclic drug benznidazole. The drug nifurtimox (Lampit ®), also used to treat long, had recently discontinued its production. In the last decade, some studies have been conducted with the aim of analyzing the effects of benznidazole in the evolution of chronic heart disease in patients with chronic illness level. Some evidence suggests that this anti-parasite treatment can prevent or slow the progression of heart disease, since few patients had progression of cardiomyopathy and many patients became serologically non-reactive. Given the current situation of Chagas disease, the goals of this project involves the synthesis of analogues of benznidazole as "click chemistry" and the application of the Principle of bioisosterism, besides the evaluation of trypanocidal activity and two biological targets of interest (trypanothione reductase and trans-sialidase) of all compounds synthesized. The strategy for synthesis of analogues of the drug benznidazole involves the use of commercial starting materials: benzyl and chloroacetyl chloride. The condensation between these reagents in the presence of triethylamine in dichloromethane will provide the product containing the amide function chloromethylene terminal. Subsequently, this derivative is treated with sodium azide in DMF to replace the chlorine atom, thus forming the intermediatist azide. From this intermediate, several analogues will be generated by cyclo-addition reaction of 1,3-dipolar Huisgen (Copper (I)-catalyzed Azide-alkyne cycloaddition) (CuAAC) with several terminal alkyne (commercially available) in the presence of sulfate copper, sodium ascorbate and dimethylformamide to form 1,2,3-triazole derivative 1,4-disubstituted containing side chain (R) with great structural diversity can modulate the activities pharmacodynamics and pharmacokinetics desired.

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Filed patent(s) as a result of this research project

ANÁLOGOS DE BENZNIDAZOL E PROCESSOS DE SÍNTESE DE ANÁLOGOS DE BENZNIDAZOL BR1020130277428 - Universidade de São Paulo (USP) . Ivone Carvalho; João Santana Da Silva; Oswaldo Aparecido Galo; Renata Sesti Costa; Peterson De Andrade - October 2013, 29