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

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.

Antioxidant Activity and Genotoxic Assessment of Crabwood (Andiroba, Carapa guianensis Aublet) Seed Oils

“…Each of these was then spread on a minimum glucose agar plate. After the top agar had solidified, the plates were incubated at 37°C for 60–72 h. Each tester strain was assayed in triplicate, and the number of revertant colonies was counted for each tester strain and treatment group [ 25 ]. The results were judged to be positive when the average number of revertant colonies in each treated group increased with increase in the compound concentration, reaching at least twice the number in the negative control group [ 24 ].…”

Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis

“…This successful example, however, must be considered as an exception in the landscape of drug discovery, as the pursuing of a structure-toxicity relationship, rather than structure-activity relationship (SAR), most of the time does not lead to similar satisfactory results. Although the presence of somebody standing out of the crowd (Boechat et al, 2015 ), the extent to which the presence of a nitro group can be tolerated in a molecule that is supposed to be administered for several months, remains a matter of debate and the use of nitroaromatic drugs is generally not recommended for a long-term treatment (Patterson and Wyllie, 2014 ). In spite of that, besides delamanid and PA-824, there is a quite consistent number of molecules in the tuberculosis drug pipeline containing a nitro group, such as nitazoxanide (Shigyo et al, 2013 ) currently in phase II clinical trials, mentioned for the sake of information, and the recently released benzothiazinones BTZ-043 and PBTZ-169, that will be discussed later more in details.…”

In silico toxicology: From structure–activity relationships towards deep learning and adverse outcome pathways

“…Although widely known as a structural alert, the nitro group is often used in therapeutics (e.g., cancer therapeutics) as a functional group providing reactivity towards the target . However, it is also known that by structural modification of such compounds the genotoxicity can be reduced, if not abolished …”