Elaborate ligand-based modeling reveals new human neutrophil elastase inhibitors

Abstract

Human neutrophil elastase inhibitors (HNE-Is) have been recently implicated in inflammatory diseases. Accordingly, we applied a drug discovery workflow to unveil novel inhibitory HNE leads via combining pharmacophore modeling, quantitative structure-activity relationship (QSAR) analysis, and in silico screening. We employed the pharmacophoric models and associated QSAR equation to screen the National Cancer Institute (NCI) list of compounds. Virtual screening identified 14 novel leads from NCI compounds. The most potent hit 126 exhibited 93 % inhibition at 10 lM.

A unified approach toward the rational design of selective low nanomolar human neutrophil elastase inhibitors

“…Greene et al 13 built a pharmacophoric model based on the interactions of the crystallographic complex between HNE and methoxysuccinyl-Ala-Ala-Pro-alanine inhibitor, nevertheless no hit activities were reported for validation purpose. Habash et al 14 recently also reported a pharmacophoric model based on a known inhibitor training set leading to hit identication with discreet mM activities. In the present work we generate a ligand-based pharmacophoric model with MOE (Molecular Operating Environment) soware.…”

Facile Synthesis of Regioisomeric N‐Alkyl Substituted 3‐Methylene‐3,4‐dihydroquinoxalin‐2(1H)‐ones

“…Enaminones bearing a 3,4‐dihydroquinoxalin‐2(1 H )‐one core (QOs) are a promising class of biologically active compounds. They were found to exhibit anticancer, anti‐inflammatory, antidiabetic, analgesic, antiviral, and antimicrobial activities (Figure ). In addition, these compounds are versatile and available building blocks enabling synthesis of various quinoxaline‐based heterocyclic systems…”

“…In addition, these compounds are versatile and available building blocks enabling synthesis of various quinoxaline-based heterocyclic systems. [7] General synthetic approaches to QOs involve interaction of acylpyruvic acids I, [1a,6a,b,7a] furan-2,3-diones II, [8] and acetylenedicarboxylates III [6d] with o-phenylenediamines, various condensations of quinoxalin-2(1H)-ones IV [2,9] (Scheme 1).…”

“…General synthetic approaches to QOs involve interaction of acylpyruvic acids I , furan‐2,3‐diones II , and acetylenedicarboxylates III with o ‐phenylenediamines, various condensations of quinoxalin‐2(1 H )‐ones IV (Scheme ).…”

Switchable highly regioselective synthesis of 3,4-dihydroquinoxalin-2(1H)ones from o-phenylenediamines and aroylpyruvates

“…Mashevskaya et al reported about an antimicrobial activity for compound 6 at 1 mg/mL for S. aureus P-209 and E. coli M 17 strains [ 11 ]. Several recent studies have identified 3,4-dihydroquinoxalin-2(1 H )-ones 7–10 as hits for distinct biological targets [ 12 – 20 ], particularly antidiabetic 7 [ 20 ], anticancer 8 [ 18 ], anti-inflammatory 9 [ 16 ], and antibacterial 10 [ 19 ] ( Fig. 1 ).…”