Studies of genotoxicity and mutagenicity of nitroimidazoles: demystifying this critical relationship with the nitro group

Núbia Boechat,Israel Felzenszwalb,Günter Haufe,Alcione S Carvalho,Taline Ramos Conde,Francisco Vc Mello,Claudia Af Aiub,Kelly Salomão,Solange L De Castro,Helena Ps Zamith,Carlos F Araujo-Lima,Rolf Skupin

doi:10.1590/0074-02760140248

Abstract

Nitroimidazoles exhibit high microbicidal activity, but mutagenic, genotoxic and cytotoxic properties have been attributed to the presence of the nitro group. However, we synthesised nitroimidazoles with activity against the trypomastigotes of Trypanosoma cruzi, but that were not genotoxic. Herein, nitroimidazoles (11-19) bearing different substituent groups were investigated for their potential induction of genotoxicity (comet assay) and mutagenicity (Salmonella/Microsome assay) and the correlations of these effects with their trypanocidal effect and with megazol were investigated. The compounds were designed to analyse the role played by the position of the nitro group in the imidazole nucleus (C-4 or C-5) and the presence of oxidisable groups at N-1 as an anion receptor group and the role of a methyl group at C-2. Nitroimidazoles bearing NO2 at C-4 and CH3 at C-2 were not genotoxic compared to those bearing NO2 at C-5. However, when there was a CH3 at C-2, the position of the NO2 group had no influence on the genotoxic activity. Fluorinated compounds exhibited higher genotoxicity regardless of the presence of CH3 at C-2 or NO2 at C-4 or C-5. However, in compounds 11 (2-CH3; 4-NO2; N-CH2OHCH2Cl) and 12 (2-CH3; 4-NO2; N-CH2OHCH2F), the fluorine atom had no influence on genotoxicity. This study contributes to the future search for new and safer prototypes and provide.

Highlights

The class of nitroimidazoles includes compounds that are important antiparasitic agents, which have a broad spectrum of action and high biological activity
This study may serve as a guide to the search for new lead compounds for the chemotherapy of human trypanosomiasis and may identify safer compounds that may serve as the basis for investigation into the mutagenic activity of nitroimidazoles
Nitroimidazoles have been clinically used for chemotherapy against several parasites, the mechanisms underlying their genotoxic and biological activities are not fully understood

Summary

Introduction

The class of nitroimidazoles includes compounds that are important antiparasitic agents, which have a broad spectrum of action and high biological activity. The 2-nitroimidazole benznidazole (BZ) (8) (Fig. 2) and nifurtimox (NFX) are the only available drugs for the treatment of Chagas disease These nitro derivatives exhibit poor activity in the late chronic phase, with severe collateral effects and limited efficacy against different parasitic isolates, justifying the urgent need to identify alternatives to treat chagasic patients (Soeiro & de Castro 2011, Urbina 2014). This disease is caused by Trypanosoma cruzi and affects approximately eight million individuals in Latin America. This study may serve as a guide to the search for new lead compounds for the chemotherapy of human trypanosomiasis and may identify safer compounds that may serve as the basis for investigation into the mutagenic activity of nitroimidazoles

Methods

Results

Conclusion