Imidazole is a secondary amine?

Root Causes Storage (Stability)
#1

Dear all,

How would you consider this structure below (2-Methylimidazole):

Captura imidazole

Could it be considered as a secondary amine source? or would it be outside of the scope of nitrosamine guidelines?
Thanks in advance!
Victoria

#2

Both N atoms are part of the aromatic system. The nitrogen in the NH group is non basic as the lone pair electrons are part of the resonance structure. It is known that for a non basic nitrogen it is difficult or not possible to form a nitrosamine and if it does, it cannot have the same carcinogenic mechanism as typical nitrosamines, based on alfa-hydroxylation and C-N cleavage as this would require breaking the aromaticity.
Check out this reference:

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#3

Great explanation, it seemed to me that it would not be possible to form nitrosamine, but now is more clear for me.
Thanks for the article!
Victoria

#4

Please just consider that as per EMA guideline at least, you will need actual data indicating it was not possible to synthetize an specific nitrosamine if after your risk assesment the nitrosamine is realistically expected or nor enough evidence to dismiss the risk.

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#5

Thanks so much! The corresponding N-nitrosocompound is commercially available but as mentioned before, it is not a real N-nitrosamine structure. Thanks!!!

#6

I believe @David can explained further the details of why we did not included in our assessment of the landscape publication. A good reference is also the adobo et al publication

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#7

I can indeed - as a basic secondary amine, a nitrosated imidazole can be formed. However, it’s nigh-on impossible for the ultimate genotoxic diazonium to form, since that would require destruction of the aromatic system.

Nitrosated pyrrole-type nitrogens can be mutagenic, but the mechanism is completely different - they are reduced (possibly via bacterial nitroreductases) to the aromatic hydroxylamine; an intermediate that may be familiar from the aromatic amine context. This then generates a nitrenium ion which is may be genotoxic, depending on substitution. This is the same mechanism as aromatic C-nitroso compounds can undergo, so in practical terms the N vs C nature of the nitrosated atom is less important than the fact it is aromatic, as we would perhaps expect. This different mechanism means that they are not expected to be of cohort-of-concern level potency, if positive.

We discuss this further - with a figure - in the recent OPRD paper here: https://pubs.acs.org/doi/10.1021/acs.oprd.3c00008

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#8

I am joining late in this conversation. There were too many things going on this week. I have had several quesitons with drugs like Etomidate, DEXMEDETOMIDINE and numerous others, which have imidazole moieties. Nitroso imidazoles form easily and some of them are potent carcinogens, especially amino imidazoles. Amino imidazoles are formed when we cook meat at high temperature. But they do not act by alpha hydroxylation though. In my opinion, we need to draw a line. Nitroso imidazoles are part the “cohort” but they may be given a lower priority in the current situation as the guidance documents talk of nitrosamines, and this is not a “nitrosamine”.

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#9

Thanks for your brilliant explanation!
I’ll try to access the article!
So as a summary, a nitrosated imidazole (which is not a not a real nitrosamine) can be formed. However, the mechanisch of mutagenicty and the “cohort-of-concern” potency would be different (lower for potency) for this Nitrosated imidazole when compared with a tipical nitrosamine structure.
Thanks again for your feedback!
Victoria

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#10

Thanks for your feedback! Agree, Nitroso imidazoles are within the “cohort” but not in the first place… :slight_smile:

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