Design and synthesis of novel series of pyrrole based chemotypes and their evaluation as selective aldose reductase inhibitors. A case of bioisosterism between a carboxylic acid moiety and that of a tetrazole

Bioorg Med Chem. 2010 Mar 15;18(6):2107-2114. doi: 10.1016/j.bmc.2010.02.010. Epub 2010 Feb 11.

Abstract

Pyrrolyl-propionic and butyric-acid derivatives 1 and 2 were synthesized in order to study the effect of the variation of the methylene chain in comparison to the previously reported pyrrolyl-acetic acid compound I, which was found as potent aldose reductase inhibitor, while the pyrrolyl-tetrazole derivatives 3-5 were prepared as a non-classical bioisosteres of a carboxylic acid moiety. Also, pyrrolyl-tetrazole isomers 6 and 7 without an alkyl chain between the two aromatic rings were synthesized. The in vitro aldose reductase inhibitory activity of the prepared 1-7 compounds were estimated and compared with that of the initial compound (I). Overall, the data indicate that the presented chemotypes 6 and 7 are a promising lead compounds for the development of selective aldose reductase inhibitors, aiming to the long-term complications of diabetes mellitus.

MeSH terms

  • Aldehyde Reductase / antagonists & inhibitors*
  • Animals
  • Carboxylic Acids / chemistry*
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Male
  • Molecular Structure
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Rats
  • Rats, Inbred F344
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tetrazoles / chemistry*

Substances

  • Carboxylic Acids
  • Enzyme Inhibitors
  • Pyrroles
  • Tetrazoles
  • 1H-tetrazole
  • Aldehyde Reductase