Virtual Combinatorial Library Design, Synthesis and In vitro Anticancer Assessment of -2-Amino-3-Cyanopyridine Derivatives

Comb Chem High Throughput Screen. 2018;21(2):138-148. doi: 10.2174/1386207321666180228113925.

Abstract

Aim and objective: For the development of new class of anticancer agents, a series of novel 2-amino-3-cyanopyridine derivatives were designed from virtual screening with Glide program by setting Topoisomerase II as the target.

Materials and methods: The top ranked ten molecules from the virtual screening were synthesized by microwave assisted technique and investigated for their cytotoxic activity against MCF-7 and A- 549 cell lines by using sulforhodamine B assay method.

Results: The most active compound 2-amino-4-(3,5-dibromo-4-hydroxyphenyl)-6-(2,4- dichlorophenyl) nicotinonitrile (CG-5) showed significant cytotoxic profile with (LC50 = 97.1, TGI = 29.9 and GI50 = <0.1 µM) in MCF-7 and (LC50= 93.0, TGI= 50.0 and GI50= <7 µM) in A-549 cell lines. A molecular docking study was performed to explore the binding interaction of CG-5with the active site of Topoisomerase II.

Conclusion: It can be concluded that halogen substituent pyridine ring was benefit for cytotoxicity.

Keywords: SRB protein assay; Virtual screening; combiGlide; derivatives; topoisomerase II..

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Catalytic Domain
  • Combinatorial Chemistry Techniques / methods*
  • DNA Topoisomerases, Type II / drug effects
  • DNA Topoisomerases, Type II / metabolism
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • MCF-7 Cells
  • Microwaves
  • Molecular Docking Simulation
  • Rhodamines / chemistry

Substances

  • Antineoplastic Agents
  • Rhodamines
  • lissamine rhodamine B
  • DNA Topoisomerases, Type II