Structural Alert: Benzimidazoles


An informative letter, just published by a team from Novartis, highlights the risk of suitably substituted benzimidazoles acting as latent precursors to reactive ortho-iminoquinone species.  The example they report (see structure on left below) was Ames positive and exhibited time-dependent inhibition of CYP3A4.

In this example they found that replacing, or removing one or both of, the metabolically labile ortho-methyl substituents led to Ames negative compounds (disubstitution being postulated to conformationally predispose one of the methyls to metabolism) and similarly, removing one of the imidazole nitrogens (to give the indole shown above), also prevented formation of the putative reactive ortho-iminoquinone species (a species with close analogy to ortho-quinones, which are known to carry a reactive metabolite risk) and hence also resulted in an Ames negative analogue.

The above hypothesis held up in analogues incorporating the minimal toxicophore and the risk could be mitigated in a similar manner.  Whilst this is a particular case worth making a note of, there is clearly also a concern that other suitably substituted benzimidazoles could carry a similar risk.

Advertisements
This entry was posted in Toxicology and tagged , , , , , , , . Bookmark the permalink.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s