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Design, synthesis, and biological evaluation of novel imidazole derivatives possessing terminal sulphonamides as potential BRAFV600Einhibitors.

Abstract：

:BRAFV600E mutation has been detected in various malignant tumours. Developing of potent BRAFV600E 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 IC50 values over each of the 60 cell lines. The selected candidates exhibited promising activity with mean IC50 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 IC50 values of compounds 14h and 16e against Melanoma cancer cell lines are 1.8 µM and 1.88 µM, respectively. In addition, BRAFV600E kinase inhibitory activity was determined for each derivative. Compounds 15i, 15j, 16a, and 16d were the most potent inhibitors against BRAFV600E with IC50 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_name

Bioorg Chem

journal_title

Bioorganic chemistry

authors

Ali EMH,Abdel-Maksoud MS,Ammar UM,Mersal KI,Ho Yoo K,Jooryeong P,Oh CH

doi

10.1016/j.bioorg.2020.104508

subject

Has Abstract

pub_date

2021-01-01 00:00:00

pages

104508

eissn

0045-2068

issn

1090-2120

pii

S0045-2068(20)31806-X

journal_volume

106

pub_type

杂志文章

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