Imidazopyridine-fused [1,3]diazepinones: modulations of positions 2 to 4 and their impacts on the anti-melanoma activity

Abstract

A series of 19 novel pyrido-imidazodiazepinones, with modulations of positions 2, 3 and 4 of the diazepine ring were synthesised and screened for their in vitro cytotoxic activities against two melanoma cell lines (A375 and MDA-MB-435) and for their potential toxicity against NIH-3T3 non-cancerous cells. Selected compounds were also evaluated on the NCI-60 cell line panel. The SAR study revealed that the molecular volume and the cLogP of compounds modified at position 2 were significantly correlated with the activity of these compounds on melanoma cell lines. Moreover, introduction of a heterocyclic group at position 2 or an azido-alkyl chain at position 4 led to compounds displaying a significantly different activity profile on the NCI-60 cell line panel, compared to phenyl-substituted compounds at position 2 of the diazepinone. This study provides us crucial information for the development of new derivatives active against melanoma.

Graphical Abstract

Keywords:

• Antitumor activity
• diazepinones
• imidazo[1,2-a]pyridine
• melanoma
• polyfused heterocycles

Acknowledgements

PLS thanks the Ligue Nationale Contre le Cancer for a doctoral scholarship. The authors thank the National Cancer Institute (NCI), Bethesda, Maryland, USA, for performing the anticancer testing of diazepinone compounds. The authors acknowledge the imaging facility MRI, member of the national infrastructure France-BioImaging infrastructure supported by the French National Research Agency (ANR-10-INBS-04, “Investissements d’avenir”). The authors wish to especially thank Christophe Duperray for his technical assistance within the platform. NM thanks Eva Beltrando and Sabrina Fellous for technical assistance.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was publicly funded through ANR (the French National Research Agency) under the “Investissements d’avenir” programme with the reference ANR-16-IDEX-0006 and by the “Ligue Nationale contre le Cancer (Comité de l’Hérault)”.