Novel pyrrol-2(3H)-ones and pyridazin-3(2H)-ones carrying quinoline scaffold as anti-proliferative tubulin polymerization inhibitors

• Published in: Bioorganic chemistry Vol. 80; pp. 151 - 163
• Main Authors: Abdelbaset, Mahmoud S., Abuo-Rahma, Gamal El-Din A., Abdelrahman, Mostafa H., Ramadan, Mohamed, Youssif, Bahaa G.M., Bukhari, Syed Nasir Abbas, Mohamed, Mamdouh F.A., Abdel-Aziz, Mohamed
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2018
• Subjects: Antiproliferative; BRAF Kinase; Pyridazin-3(2H)-ones; Pyrrol-2(3H)-ones; Quinoline; Tubulin polymerization; Pyridazin-3(2H)-ones; Antiproliferative; Quinoline; BRAF Kinase; Pyrrol-2(3H)-ones; Tubulin polymerization
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.06.003

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•Novel quinolinyl pyrrolone and quinolinyl pyridazinone derivatives.•Antiproliferative activity.•BRAF kinase inhibition.•Tubulin polymerization inhibitory activity.•Molecular docking into colchicine binding site.
A novel quinolinyl pyrrolone and quinolinyl pyridazinone derivatives has been synthesized and characterized using different spectroscopic and elemental analysis techniques. Most of the target compounds displayed promising antiproliferative activity; In general, the pyrrolone derivatives 4a-f exhibited higher antiproliferative activity than their corresponding pyridazinone. The pyrrolone 4f showed outstanding antiproliferative activity with moderate selectivity against CNS and renal cancer with selectivity ratio of 3.49 and 3.56, respectively. Compound 4e and 5d experienced tubulin polymerization inhibitory activity comparable to that of vincristine while 4c, 4e and 4d showed good BRAF kinase inhibition compared to Erlotinib. Docking of compound 4e into colchicine binding site and biological assay results revealed that these compounds act mainly through tubulin polymerization inhibitory mechanism and can exhibit pre G1 apoptosis and cell cycle arrest at G2/M phase.