Design, synthesis and docking study of novel tetracyclic oxindole derivatives as α-glucosidase inhibitors

Kailin Han; Yashan Li; Yazhou Zhang; Yuou Teng; Ying Ma; Meiyan Wang; Runling Wang; Weiren Xu; Qingwei Yao; Yongmin Zhang; Haijuan Qin; Hua Sun; Peng Yu

doi:10.1016/j.bmcl.2015.02.031

Design, synthesis and docking study of novel tetracyclic oxindole derivatives as α-glucosidase inhibitors

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1471-5. doi: 10.1016/j.bmcl.2015.02.031. Epub 2015 Feb 21.

Authors

Kailin Han¹, Yashan Li¹, Yazhou Zhang¹, Yuou Teng¹, Ying Ma², Meiyan Wang², Runling Wang², Weiren Xu³, Qingwei Yao⁴, Yongmin Zhang⁵, Haijuan Qin⁶, Hua Sun⁷, Peng Yu⁸

Affiliations

¹ Key Laboratory of Industrial Fermentation Microbiology (Tianjin University of Science and Technology), Ministry of Education, Tianjin 300457, China; Tianjin Key Laboratory of Industry Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China; Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin 300457, China.
² Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
³ Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research (TIPR), Tianjin 300193, China.
⁴ Sphinx Scientific Laboratory, 1250 East State Street, Sycamore, IL 60178, USA.
⁵ Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin 300457, China.
⁶ Key Laboratory of Industrial Fermentation Microbiology (Tianjin University of Science and Technology), Ministry of Education, Tianjin 300457, China.
⁷ Key Laboratory of Industrial Fermentation Microbiology (Tianjin University of Science and Technology), Ministry of Education, Tianjin 300457, China; Tianjin Key Laboratory of Industry Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China; Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin 300457, China. Electronic address: sunhua@tust.edu.cn.
⁸ Key Laboratory of Industrial Fermentation Microbiology (Tianjin University of Science and Technology), Ministry of Education, Tianjin 300457, China; Tianjin Key Laboratory of Industry Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China; Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of Science and Technology, Tianjin 300457, China. Electronic address: yupeng@tust.edu.cn.

PMID: 25759031
DOI: 10.1016/j.bmcl.2015.02.031

Abstract

A series of novel tetracyclic oxindole derivatives were synthesized via tandem Suzuki coupling-Michael addition reaction catalyzed by palladium. Twenty derivatives were designed and synthesized in 6-8 steps in 8-20% overall yields. Their structures were confirmed by (1)H, (13)C NMR and LC/MS. These compounds were evaluated for α-glucosidase inhibitory activity in vitro. Compounds 7c, 7d, 7e, 7g, 7h, and 7i exhibited IC50 values of 32.3, 12.1, 15.7, 29.0, 16.0, and 4.8 μM, respectively, with potency all higher than that of the control standard acarbose (IC50=115.8 μM). Molecular docking studies revealed the existence of potential hydrogen bonding and hydrophobic interaction between the enzyme and the active compound 7i.

Keywords: Docking study; Phenanthridine derivatives; SAR study; Tetracyclic isatins; α-Glucosidase inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Drug Design*
Glycoside Hydrolase Inhibitors / chemical synthesis
Glycoside Hydrolase Inhibitors / chemistry
Glycoside Hydrolase Inhibitors / pharmacology*
Indole Alkaloids / chemical synthesis
Indole Alkaloids / chemistry
Indole Alkaloids / pharmacology*
Molecular Docking Simulation*
Molecular Structure
Structure-Activity Relationship
alpha-Glucosidases / metabolism*

Substances

Glycoside Hydrolase Inhibitors
Indole Alkaloids
alpha-Glucosidases