TimTec Diversity Library of 10,000 compounds was screened in research collaboration between Department of Veterinary Molecular Biology at Montana State UniVersity, Bozeman, Montana, and Department of Chemistry at Altai State Technical UniVersity, Barnaul, Russia.

A screen of the library identified 26 test compounds and explored their effects on human neutrophil function.

Schepetkin, I., et al., High-throughput Screening for Small-molecule Activators of Neutrophils: Identification of Novel N-Formyl Peptide Receptor Agonists.  Mol. Pharmacol. 71: 1061-1074 (2007)

Abstract

We screened a chemolibrary of drug-like molecules for their ability to activate reactive oxygen species (ROS) production in murine phagocytes, and we identified 26 novel compounds with potent neutrophil activating properties. We used substructure screening, fragment-focusing, and structure-activity relationship analyses to further probe the parent library and defined at least two groups of activators of ROS production in murine neutrophils: t-butyl benzene and thiophene-2-amide-3-carboxylic ester derivatives. Further studies of the active compounds revealed 11 compounds that activated ROS production in human neutrophils, and six of these compounds also activated intercellular Ca2 mobilization and chemotaxis in human neutrophils. Of the latter compounds, compound 14 (1,3-benzodioxolane-5-carboxylic acid 4[1]-benzyloxy-3[1]-ethoxybenzylidene-hydrazide) activated neutrophils at nanomolar concentrations, and Ca2 mobilization was inhibited by pertussis toxin and N-t-butoxycarbonyl-Phe-Leu-Phe-Leu-Phe (Boc-2), an antagonist of formyl peptide receptors (FPR/FPRL1). Likewise, activation by compound 14 was desensitized after N-formyl-Met-Leu-Phe pretreatment. Similar biological activities were found for compound 104 (1,3-benzodioxolane-5-carboxylic acid 3[1]-bromo-5[1]-ethoxy-4[1]-hydroxybenzylidenehydrazide), an analog of compound 14. Furthermore, conformational analysis of the activators of chemotaxis and Ca2mobilization showed a high degree of similarity in distances between pharmacophore points of compounds 14 and 104 with a model of FPR published by Edwards et al. (Mol Pharmacol 68:1301–1310, 2005), indicating that conformational features of the agonists identified here are structurally compatible with steric constraints of the ligand-binding pocket of the receptor. Based on these results, we conclude that compounds 14 and 104 represent novel small-molecule agonists of FPR. These studies enhance our understanding of FPR ligand/receptor interactions and structure/activity relationships of phagocyte agonists.

Activators of Neutrophils analogs

 

Activators of Neutrophils


ST044918
C17H20N4O5S
392.44
ST032745
C15H18N2O5
306.32
ST031779
C22H23ClN6O
440.54

ST044255
C19H14F3N3O2
373.34
ST025080
C16H16BrNO3S
382.28
ST005548
C16H15N5OS
305.38

ST018377
C25H44N4O2
432.66
ST036732
C18H21ClN6O3S2
468.99
ST043379
C18H20N2O4
328.37

ST014842
C18H19NO5S
361.42
ST026338
C9H8N2OS2
224.3
ST009296
C25H30N4O2S
450.61

ST030659
C16H17ClN2O2
304.78
ST031474
C20H16ClN3O
349.82
ST030793
C18H22N2O2S
330.45

ST024194
C11H16N2S
208.33
ST020520
C23H20N2O5
404.43
ST031274
C21H14Br2N2O4
518.16

ST028364
C15H11Cl2N5OS
380.26

 

Activators of Neutrophils analogs

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