Synthesis and anti-Trypanosoma cruzi activity of diaryldiazepines.

Júlio Menezes,Luana Vaz,Cláudia Carneiro,Paula De Abreu Vieira,Jason Taylor,Kátia Da Silva Fonseca

doi:10.3390/molecules20010043

Júlio Menezes, Luana Vaz + Show 4 more

Open Access

https://doi.org/10.3390/molecules20010043

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Abstract

Chagas disease is a so-called “neglected disease” and endemic to Latin America. Nifurtimox and benznidazole are drugs that have considerable efficacy in the treatment of the acute phase of the disease but cause many significant side effects. Furthermore, in the Chronic Phase its efficiency is reduced and their therapeutic effectiveness is dependent on the type of T. cruzi strain. For this reason, the present work aims to drive basic research towards the discovery of new chemical entities to treat Chagas disease. Differently substituted 5,7-diaryl-2,3-dihydro-1,4-diazepines were synthesized by cyclocondensation of substituted flavones with ethylenediamine and tested as anti-Trypanosoma cruzi candidates. Epimastigotes of the Y strain from T. cruzi were used in this study and the number of parasites was determined in a Neubauer chamber. The most potent diaryldiazepine that reduced epimastigote proliferation exhibited an IC50 value of 0.25 μM, which is significantly more active than benznidazole.

Highlights

Seven-membered heterocycles with two nitrogen’s in a 1,4-relationship are classified as diazepines.Diazepines are well known for their unique pharmacological activity and in particular, the1,4-benzodiazepines are especially recognized for their effects on the central nervous system [1]
In the last 10 years, a variety of 1,4-diazepines have been reported for various biological activities, such as anti-schistosomal activity [2], apoptosis inhibitors [3], Nox4/Nox1 inhibitors [4] and anticonvulsant activity, [5] amongst others
In general, diaryldiazepines have been underexplored for other types of diseases and this is surprising given the possibility to modulate its activity by incorporating different substituents on the phenyl rings (Figure 1)

Summary

Introduction

Seven-membered heterocycles with two nitrogen’s in a 1,4-relationship are classified as diazepines. Known as Chagas disease [7], is included in the NTD list and is endemic to 21 Latin American countries [8,9]. The two drugs currently available for treating Chagas disease are nifurtimox and benznidazole, which are chemically related nitro-heterocycles (Figure 2). They both result in many significant side effects such as oedema, fever, rash, agranulocytosis and neurotoxicity. The therapeutic effectiveness of nifurtimox and benznidazole is dependent on the type of T. cruzi strain, since certain strains are more resistant than others [11]. Promising results are indicated by potencies that are either equal to or better than benznidazole with varying degrees of mammalian cell toxicity observed depending on the compound class (Figure 3). The aryloxyindoles stand out for their high potency but in general, IC50 values in the range of 4–30 μM have been considered promising candidate leads

Results and Discussion

Experimental Section

Chemistry

Anti-Trypanosoma cruzi Activity