Pharmacophore-based discovery of 2-(phenylamino)aceto-hydrazides as potent eosinophil peroxidase (EPO) inhibitors

Abstract

There is an increasing interest in developing novel eosinophil peroxidase (EPO) inhibitors, in order to provide new treatment strategies against chronic inflammatory and neurodegenerative diseases caused by eosinophilic disorder. Within this study, a ligand-based pharmacophore model for EPO inhibitors was generated and used for in silico screening of large 3 D molecular structure databases, containing more than 4 million compounds. Hits obtained were clustered and a total of 277 compounds were selected for biological assessment. A class of 2-(phenyl)amino-aceto-hydrazides with different substitution pattern on the aromatic ring was found to contain the most potent EPO inhibitors, exhibiting IC50 values down to 10 nM. The generated pharmacophore model therefore, represents a valuable tool for the selection of compounds for biological testing. The compounds identified as potent EPO inhibitors will serve to initiate a hit to lead and lead optimisation program for the development of new therapeutics against eosinophilic disorders.

Direct conversion of amino acids to oxetanol bioisosteres via photoredox catalysis

“…This methodology is applicable to a wide range of N-aryl a-amino acids, a motif which has been reported to have a variety of potential therapeutic applications in infectious disease, inammation, neurodegeneration, and metabolic and gastrointestinal diseases. [47][48][49] The substrate scope of the Cr-free reaction also includes N,N-dialkyl a-amino acid substrates. Efforts to expand the substrate scope further to other carboxylic acids are under active investigation in our lab.…”

Peroxidasin Inhibition by Phloroglucinol and Other Peroxidase Inhibitors

“…Phloroglucinol, lomefloxacin, thioridazine, metoclopramide and hydralazine-vanillin are approved drugs and the latter four were used in inhibitor studies of MPO. A quinazoline compound, two phthalazine compounds and three benzodioxol compounds were identified as inhibitors of MPO [47,53], whereas two (phenylamino)acetic acid (F-PAAA and Cl-PAAA) compounds and two (phenylamino)acetic hydrazides (F-PAAH and Cl-PAAH) were previously recognized as potent EPO inhibitors [54]. Dopamine, which is a peroxidase substrate, was also examined in this study.…”

“…Hydralazine-vanillin, quinazoline, lomefloxacin, thioridazine and metoclopramide were from Sigma. Benzodioxol 1, benzodioxol 2, benzodioxol 3, phthalazine 1 and phthalazine 2 were synthesized and the purity and quality were controlled by NMR spectroscopy, as described previously [47,[54][55][56][57]. Structures of compounds are summarized in Table 1.…”

Challenges and Strategies for Synthesizing Glutamyl Hydrazide Containing Peptides

“…5 We have previously reported that a simple hydrazide core (6) can covalently inhibit the lysyl oxidase enzyme with less off-target inhibition than simple arylhydrazine or alkylhydrazine inhibitors. 6 Figure 1 Some biologically active primary hydrazides [1][2][3][4][5][6] Unnatural Amino Acid Warheads One general strategy for developing selective enzyme inhibitors is to incorporate a functionally active unnatural amino acid into a peptide chain. This warhead group provides the key functionality of the inhibitor, while the se-…”

“…1 Schuster et al have reported that hydrazide 2 inhibits the eosinophil peroxidase enzyme with an IC 50 value of 10 nM. 2 This enzyme is a target for treating inflammatory and neurodegenerative diseases that are caused by eosinophilic disorders. Artico and co-workers have reported that hydrazide 3 irreversibly inhibits the bovine serum amine oxidase enzyme with a 30-minute IC 50 value of 100 nM and with <50-fold selectivity for that enzyme versus other tested amine oxidases.…”