2. Academic Validation
  3. Synthesis, bioevaluation and molecular dynamics of pyrrolo-pyridine benzamide derivatives as potential antitumor agents in vitro and in vivo

Synthesis, bioevaluation and molecular dynamics of pyrrolo-pyridine benzamide derivatives as potential antitumor agents in vitro and in vivo

  • Eur J Med Chem. 2022 Apr 5;233:114215. doi: 10.1016/j.ejmech.2022.114215.
Jianqing Zhang 1,  Jintian Dai 2,  Xin Lan 3,  Ying Zhao 3,  Feiyi Yang 4,  Han Zhang 4,  Sheng Tang 4,  Guang Liang 5,  Xu Wang 6,  Qidong Tang 7
Affiliations

Affiliations

  • 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, PR China; Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, Jiangxi, PR China.
  • 2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, PR China; Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, Jiangxi, PR China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325001, Zhejiang, PR China.
  • 3 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, PR China.
  • 4 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, Jiangxi, PR China.
  • 5 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, PR China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325001, Zhejiang, PR China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, 325001, Zhejiang, PR China.
  • 6 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, PR China. Electronic address: sunrim@163.com.
  • 7 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, PR China; Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, Jiangxi, PR China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325001, Zhejiang, PR China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, 325001, Zhejiang, PR China. Electronic address: tangqidongcn@126.com.
PMID: 35227978 DOI: 10.1016/j.ejmech.2022.114215
Abstract

A total of 27 novel pyrrolo-pyridine benzamide derivatives were designed, synthesized and biologically evaluated. 14 of these derivatives were superior to Cabozantinib in cytotoxic assay, and compound 21 exhibited the best antitumor effect in vitro and vivo. Apoptosis activity was implemented by compound 21 on A549 cells, especially for the greatly enhanced late Apoptosis compared with the control group (8.13% vs 4.49%), which was superior to that of Cabozantinib (6.89%). Similarly, 21 stagnated the A549 cells arrest in the two cell distribution phases (G0/G1 and G2/M) in dose-dependence manner. In addition, compound 21 could inhibit c-Met expression compared with Cabozantinib at the same concentration (10 μM). The results of molecular docking and dynamics study demonstrated that compound 21 formed four key hydrogen bonds with c-Met kinase. And key Amino acids Met1160, Phe1134 and Phe1223 played a key functional role in the binding free energy. Furthermore, 21 exhibited high antitumor efficacy in tumor growth inhibition rate, which was superior to Cabozantinib (64.5% vs 47.9%). Overall, compound 21 could be considered as a promising antitumor agent.

Keywords

Activity; Molecular dynamics; Pyrrolo-pyridine benzamide derivatives; SARs.

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