2. Academic Validation
  3. Design and synthesis of novel 6-hydroxy-4-methoxy-3-methylbenzofuran-7-carboxamide derivatives as potent Mnks inhibitors by fragment-based drug design

Design and synthesis of novel 6-hydroxy-4-methoxy-3-methylbenzofuran-7-carboxamide derivatives as potent Mnks inhibitors by fragment-based drug design

  • Bioorg Med Chem. 2018 Sep 1;26(16):4602-4614. doi: 10.1016/j.bmc.2018.05.004.
Shuxiang Wang 1,  Bo Li 1,  Bo Liu 1,  Min Huang 1,  Deyi Li 1,  Lihong Guan 1,  Jie Zang 1,  Dan Liu 2,  Linxiang Zhao 3
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: sammyld@163.com.
  • 3 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: linxiang.zhao@vip.sina.com.
PMID: 30115493 DOI: 10.1016/j.bmc.2018.05.004
Abstract

A novel series of 6-hydroxy-4-methoxy-3-methylbenzofuran-7-carboxamide derivatives featured with various C-2 substituents were designed and synthesized as Mnks inhibitors through fragment-based drug design. Among them, 5b, 5i, 5o and 8k showed the best MNK2 inhibitory activity with IC50 values of 1.45, 1.16, 3.55 and 0.27 μM, respectively. And these compounds inhibited the activity of MNK1 at the same time. Furthermore, compounds 5o and 8k exhibited anti-proliferative effects to human leukemia Cancer THP-1 and MOLM-13 cell lines and colon Cancer HCT-116 cell line. Moreover, Western blot assay suggested that 8k could decrease the levels of p-eIF4E in a dose-dependent manner in HCT-116 cells. Docking studies demonstrated strong interactions between 8k and MNK2. Therefore, this unique benzofuran scaffold demonstrated great potential to be further explored as potent Mnks inhibitors with improved potency.

Keywords

6-Hydroxy-4-methoxy-3-methylbenzofuran-7-carboxamide derivatives; Anti-proliferative effects; Fragment-based drug design; Mnks inhibitors.

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