Design, synthesis, in vitro potent antiproliferative activity, and kinase inhibitory effects of new triarylpyrazole derivatives possessing different heterocycle terminal moieties

• Published in: Journal of enzyme inhibition and medicinal chemistry 2019-01, Vol.34 (1), p.1534-1543
• Main Authors: Gamal El-Din, Mahmoud M., El-Gamal, Mohammed I., Abdel-Maksoud, Mohammed S., Yoo, Kyung Ho, Oh, Chang-Hyun
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Humans; Molecular Structure; morpholine; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - metabolism; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Research Paper; Structure-Activity Relationship; substituted piperazine; triarylpyrazole; V600E-B-RAF
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2019.1653292

A new series of triarylpyrazole derivatives having different heterocycle terminal groups have been designed and synthesised. Compounds 1h-j and 1l exhibited the highest mean percentage inhibition against the 58 cancer cell lines at a concentration of 10 μM, and thus were next examined in 5-dose testing mode to detect their IC 50 value. The four compounds showed stronger antiproliferative activities upon comparing their results with sorafenib as a reference compound. Among them, compounds 1j and 1l possessing N-ethylpiperazinyl and N-benzylpiperazinyl terminal moiety through ethylene linker showed the greatest values of mean percentage inhibition (97.72 and 107.18%, respectively) over the 58-cell line panel at 10 μM concentration. The IC 50 values of compound 1j over several cancer cell lines were in submicromolar scale (0.26 ∼ 0.38 μM). Moreover, the compounds 1j and 1l showed highly inhibitory activities (99.17 and 97.92%) against V600E-B-RAF kinase.