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

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 35; no. 1; pp. 935 - 949
• Main Authors: Baccon-Sollier, Paul Le, Malki, Yohan, Maye, Morgane, Ali, Lamiaa M. A., Lichon, Laure, Cuq, Pierre, Vincent, Laure-Anaïs, Masurier, Nicolas
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 01.01.2020; Informa Healthcare; Taylor & Francis Group
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Azepines - chemistry; Azepines - pharmacology; Biochemistry & Molecular Biology; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; diazepinones; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; imidazo[1,2-a]pyridine; Imidazoles - chemistry; Imidazoles - pharmacology; Life Sciences; Life Sciences & Biomedicine; melanoma; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Mice; Molecular Structure; NIH 3T3 Cells; Pharmacology & Pharmacy; polyfused heterocycles; Pyridines - chemistry; Pyridines - pharmacology; Research Paper; Science & Technology; Structure-Activity Relationship; imidazo; Antitumor activity; diazepinones; 2-a]pyridine; melanoma; EFFICIENT; polyfused heterocycles; imidazo[1,2-a]pyridine
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2020.1748024

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.