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Design, synthesis, and biological evaluation of novel imidazole derivatives possessing terminal sulphonamides as potential BRAFV600E inhibitors

Ali, Eslam M.H.; Abdel-Maksoud, Mohammed S.; Ammar, Usama M.; Mersal, Karim I.; Ho Yoo, Kyung; Jooryeong, Park; Oh, Chang-Hyun


Eslam M.H. Ali

Mohammed S. Abdel-Maksoud

Karim I. Mersal

Kyung Ho Yoo

Park Jooryeong

Chang-Hyun Oh


BRAF V600E mutation has been detected in various malignant tumours. Developing of potent BRAF V600E inhibitors is considered a leading step in the way to cure different cancer types. In the current work, a series of 38 4-(1H-imidazol-5-yl)pyridin-2-amine derivatives was designed and synthesized using Dabrafenib as a lead compound for structural-guided optimization. The target compounds were evaluated as potential anticancer agents against NCI 60 human cancer cell lines. In 5-dose testing mode, two compounds 14h and 16e were tested to determine their IC 50 values over each of the 60 cell lines. The selected candidates exhibited promising activity with mean IC 50 values of 2.4 µM and 3.6 µM, respectively. Melanoma cancer cell lines exhibited the highest sensitivity after the treatment with the tested compounds 14h and 16e. The mean IC 50 values of compounds 14h and 16e against Melanoma cancer cell lines are 1.8 µM and 1.88 µM, respectively. In addition, BRAF V600E kinase inhibitory activity was determined for each derivative. Compounds 15i, 15j, 16a, and 16d were the most potent inhibitors against BRAF V600E with IC 50 76 nM, 32 nM, 35 nM, and 68 nM. The newly developed compounds represent a therapeutically promising approach for the treating various cancer types.

Journal Article Type Article
Acceptance Date Nov 19, 2020
Online Publication Date Nov 24, 2020
Publication Date 2021-01
Deposit Date Dec 11, 2022
Journal Bioorganic Chemistry
Print ISSN 0045-2068
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 106
Article Number 104508
Keywords Protein kinase inhibitors, BRAFV600E inhibitors, Anticancer, Imidazole, SAR
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