Scholarlink

<p>A new series of 1-substiuted-5,6-dichloro-2-(4-methoxyphenyl)-1<i>H</i>-benzo[<i>d</i>]imidazoles <b>10a</b>–<b>p</b> was designed and synthesized to target both BRAF<sub>WT</sub> and BRAF<sub>V600E</sub>. The design strategy ensures that these derivatives would effectively occupy the ATP binding pocket of BRAF<sub>WT/V600E</sub> kinase domains and extend over the gate area interacting through hydrogen bonding with the surrounding key amino acids Glu500 and Asp593 and to finally occupy the allosteric hydrophobic back pocket. Some synthesized derivatives demonstrated impressive potency against BRAF<sub>WT</sub> with % inhibition approaching 91% at a concentration of 10 µM. The most potent candidate <b>10h</b> demonstrated IC<sub>50</sub> values of 1.72 and 2.76 µM on BRAF<sub>WT</sub> and BRAF<sub>V600E</sub>, respectively. At the same time, the synthesized benzimidazoles <b>10a</b>–<b>p</b> were examined for their growth inhibitory activity on NCI-60 cancer cell lines. Again, compound <b>10h</b> revealed a potent GI<sub>50</sub> across a range of cancer cell lines. Moreover, it arrested cell cycle progression in HT29 colon cancer cell line at G2/M phase and induced apoptosis in the same cell line. Molecular dynamics simulations supported the validity of the design assumption, simultaneously, ADME prediction study displayed that the designed benzimidazoles exhibit promising physiochemical and drug-likeness properties as anticancer agents.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Novel 5,6-dichlorobenzimidazole derivatives as dual BRAFWT and BRAFV600E inhibitors: design, synthesis, anti-cancer activity and molecular dynamics simulations

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月21日

查看全文
  • Ahmed Temirak,
  • Ahmed M. El Kerdawy,
  • Amira M. Nageeb,
  • Heba T. Abdel-Mohsen

摘要

A new series of 1-substiuted-5,6-dichloro-2-(4-methoxyphenyl)-1H-benzo[d]imidazoles 10a–p was designed and synthesized to target both BRAFWT and BRAFV600E. The design strategy ensures that these derivatives would effectively occupy the ATP binding pocket of BRAFWT/V600E kinase domains and extend over the gate area interacting through hydrogen bonding with the surrounding key amino acids Glu500 and Asp593 and to finally occupy the allosteric hydrophobic back pocket. Some synthesized derivatives demonstrated impressive potency against BRAFWT with % inhibition approaching 91% at a concentration of 10 µM. The most potent candidate 10h demonstrated IC50 values of 1.72 and 2.76 µM on BRAFWT and BRAFV600E, respectively. At the same time, the synthesized benzimidazoles 10a–p were examined for their growth inhibitory activity on NCI-60 cancer cell lines. Again, compound 10h revealed a potent GI50 across a range of cancer cell lines. Moreover, it arrested cell cycle progression in HT29 colon cancer cell line at G2/M phase and induced apoptosis in the same cell line. Molecular dynamics simulations supported the validity of the design assumption, simultaneously, ADME prediction study displayed that the designed benzimidazoles exhibit promising physiochemical and drug-likeness properties as anticancer agents.

Graphical Abstract