Design, synthesis and biological evaluation of novel inhibitors against cyanobacterial pyruvate dehydrogenase multienzyme complex E1

Bioorg Med Chem. 2019 Jun 15;27(12):2413-2420. doi: 10.1016/j.bmc.2019.01.021. Epub 2019 Jan 22.

Abstract

Cyanobacterial pyruvate dehydrogenase multienzyme complex E1 (PDHc E1) is a potential target enzyme for finding inhibitors to control harmful cyanobacterial blooms. In this study, a series of novel triazole thiamin diphosphate (ThDP) analogs were designed and synthesized by modifying the substituent group of triazole ring and optimizing triazole-benzene linker as potential cyanobacterial PDHc E1 (Cy-PDHc E1) inhibitors. Their inhibitory activities against Cy-PDHc E1 in vitro and algicide activities in vivo were further examined. Most of these compounds exhibited prominent inhibitory activities against Cy-PDHc E1 (IC50 1.48-4.48 μM) and good algicide activities against Synechocystis PCC6803 (EC50 0.84-2.44 µM) and Microcystis aeruginosa FACHB905 (EC50 0.74-1.77 µM). Especially, compound 8d showed not only the highest inhibitory activity against Cy-PDHc E1 (IC50 1.48 μM), but also the most powerful inhibitory selectivity between Cy-PDHc E1 (inhibitory rate 98.90%) and porcine PDHc E1 (inhibitory rate only 9.54%). Furthermore, the potential interaction between compound 8d and Cy-PDHc E1 was analyzed by a molecular docking method and site-directed mutagenesis and enzymatic analysis and fluorescence spectral analysis. These results indicated that compound 8d could be used as a hit compound for further optimization and might have potential to be developed as a new algicide.

Keywords: Algicide; Cyanobacterial blooms; Inhibitor; Pyruvate dehydrogenase multienzyme component E1; Thiamin diphosphate (ThDP) analogs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Cyanobacteria / enzymology*
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Molecular Docking Simulation
  • Mutagenesis, Site-Directed
  • Pyruvate Dehydrogenase Complex / antagonists & inhibitors*
  • Pyruvate Dehydrogenase Complex / genetics
  • Pyruvate Dehydrogenase Complex / metabolism
  • Structure-Activity Relationship
  • Synechocystis / drug effects
  • Triazoles / chemistry
  • Triazoles / metabolism
  • Triazoles / pharmacology

Substances

  • Enzyme Inhibitors
  • Pyruvate Dehydrogenase Complex
  • Triazoles
  • pyruvate dehydrogenase multienzyme complex E1