N-Phenylbenzamide derivatives as alternative oxidase inhibitors: Synthesis, molecular properties, 1H-STD NMR, and QSAR

• Published in: Journal of molecular structure 2020-05, Vol.1208, p.127903, Article 127903
• Main Authors: Costa, Paulo C.S., Barsottini, Mario R.O., Vieira, Maria L.L., Pires, Bárbara A., Evangelista, Joel S., Zeri, Ana C.M., Nascimento, Andrey F.Z., Silva, Jaqueline S., Carazzolle, Marcelo F., Pereira, Gonçalo A.G., Sforça, Maurício L., Miranda, Paulo C.M.L., Rocco, Silvana A.
• Format: Article
• Language: English
• Subjects: 1H-STD NMR; Alternative Oxidase (AOX); DRX; Enzyme inhibition; NMR-based ligand screening; QSAR
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2020.127903

In the present work, 117 N-phenylbenzamides (NPDs) were prepared and evaluated against recombinant AOX from the fungal pathogen Moniliophthora perniciosa. 1H, 13C 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, 3FH, was further characterized by DRX and 1H-NMR-STD. Single crystal X-ray diffraction showed intra- and intermolecular interactions of 3FH in solid-state and elucidated its 3D structural configuration. 1H-NMR-STD allowed us to derive protein-ligand interactions in a membrane-mimetic system and evidenced an outstanding interaction of 3FH 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. [Display omitted] •Selective inhibition of AOX by N-phenylbenzamides.•1H-STD NMR experiment evidenced the ligand ability to bind at the active site.•QSAR-2D highlighted more important molecular fragments.•Lead compounds to new fungicides and neglected disease pathogens.