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
Inhibitors of Anthrax Lethal Factor
| ST003272 C10H8N2O3S 236.25 |
ST018515 C15H12O6 288.26 |
ST019413 C17H12N4O5S2 416.44 |
| ST020475 C21H13ClN2O5 408.8 |
ST020488 C21H19ClN2O3 382.85 |
ST024040 C24H18ClN3O5S2 528.01 |
| ST028252 C22H14Cl2N2O4 441.27 |
ST028971 C14H12BrNO4S2 402.29 |
ST032629 C18H11N3O5S2 413.43 |
| ST037827 C18H13N3O5S 383.38 |
ST040452 C17H16ClN5O3S2 437.93 |
ST042011 C23H12BrF3N2O6 549.26 |
| ST042187 C13H13NO3 231.25 |
ST072610 C24H15ClN2O5S2 510.98 |
|