Synthesis and biological evaluation of 4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamides and their zinc(ii) complexes as candidate antidiabetic agents

Abstract

The newly designed 1-(arylmethyl)-2,5-dihydro-4-hydroxy-5-oxo-1H-pyrrole-3-carboxamides (1a–e) were synthesized by using N-tritylated acrylamide as a starting material, and their zinc(II) complexes (10a–e) were readily prepared by simply mixing 1a–e and ZnSO₄ in the presence of LiOH. The aldose reductase (AR) inhibitory activity of 1a–e was evaluated to reveal important structural features for 2,5-dihydro-5-oxo-1H-pyrrole derivatives to exhibit high AR inhibitory activity. The in vitro insulin–mimetic activity of these complexes was evaluated from 50% inhibitory concentrations (IC₅₀) on free fatty acid (FFA) release from isolated rat adipocytes treated with epinephrine. Four out of the five newly synthesized complexes exhibited higher in vitro insulin-mimetic activities than ZnSO₄, a positive control. This study proved that the newly synthesized N₂O₂-coordination-type zinc(II) complexes based on pyrrole-3-carboxamide derivatives (1a–d) are potential hypoglycemic agents.