Evaluation of 2-( <i>1H</i> -1,2,3-triazol-1-yl) acetic acid derivatives as potential human hypoxia-inducible factor (HIF) prolyl hydroxylase domain-2 (PHD2) inhibitors

Abstract The hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) inhibitors can potentially treat ischemic and hypoxic-related diseases, as demonstrated by their use in anemia treatment. An AlphaScreen assay was utilized to assess the PHD2 inhibition of the 2-( 1H -1,2,3-triazol-1-yl)acetic acid (TA) derivatives ( 1–14 ), which were synthesized using copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction. Most of the TA derivatives did not inhibit PHD2 effectively, with compound 14 demonstrating weak inhibition at 100 µM (&gt;50 %). Docking experiments revealed that 14 forms hydrogen bond interactions with Arg 383 and binds to the PHD2 active site iron in a bidentate manner. Molecular dynamic simulation analysis shows 14 resembles but differs from the positive control inhibitor bicyclic isoquinoline (BIQ). It displays stable dynamic characteristics, with some flexible areas stabilizing upon binding to PHD2. The total binding energies for BIQ-PHD2 and 14-PHD2 were determined to be −42.90 kcal/mol and −36.08 kcal/mol, respectively. These values suggest that 14 and BIQ have similar binding affinities. In conclusion, structural changes of 14 may result in the development of an effective PHD2 inhibitor. However, most TA derivatives showed strong binding in docking studies but did not demonstrate good inhibitory activity against PHD2.