N-Phenylbenzamide Derivatives As Alternative Oxidase Inhibitors: Synthesis, Molecular Properties, H-1-Std Nmr, And Qsar

In the present work, 117 N-phenylbenzamides (NPDs) were prepared and evaluated against recombinant AOX from the fungal pathogen Moniliophthora perniciosa. H-1, C-13 NMR, FTIR, and mass spectra provided structural information on NPDs. The library compounds were tested as Alternative Oxidase inhibitors in two different assays using the model yeast Pichia pastoris: cell growth and oxygen consumption assays. The most active compound, 3(FH), was further characterized by DRX and 1H-NMR-STD. Single crystal X-ray diffraction showed intra- and intermolecular interactions of 3(FH) in solid-state and elucidated its 3D structural configuration. 1H-NMR-STD allowed us to derive protein-ligand interactions in a membranemimetic system and evidenced an outstanding interaction of 3(FH) with this enzyme. Results of both biological assays were used as input to Quantitative Structure-Activity Relationship models, which highlighted the more important molecular fragments contributions for protein-ligand interaction. (C) 2020 Elsevier B.V. All rights reserved.