Evaluating Triazole-Substituted Pyrrolopyrimidines as CSF1R Inhibitors
6-Aryl-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-4-amines have promising properties as colony-stimulating factor 1 receptor (CSF1R) inhibitors. Inspired by these antagonists, two series of 1,2,3-triazole analogues (28 compounds) were synthesized and evaluated as CSF1R inhibito...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/12/2641 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1839653217697267712 |
|---|---|
| author | Srinivasulu Cherukupalli Jan Eickhoff Carsten Degenhart Peter Habenberger Anke Unger Bård Helge Hoff Eirik Sundby |
| author_facet | Srinivasulu Cherukupalli Jan Eickhoff Carsten Degenhart Peter Habenberger Anke Unger Bård Helge Hoff Eirik Sundby |
| author_sort | Srinivasulu Cherukupalli |
| collection | DOAJ |
| description | 6-Aryl-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-4-amines have promising properties as colony-stimulating factor 1 receptor (CSF1R) inhibitors. Inspired by these antagonists, two series of 1,2,3-triazole analogues (28 compounds) were synthesized and evaluated as CSF1R inhibitors. Enzymatic IC<sub>50</sub> profiling showed that 27 of the 28 derivatives had lower IC<sub>50</sub> than the reference drug PLX-3397. Three derivatives displayed CSF1R Ba/F3 cellular IC<sub>50</sub> well below 1 µM. Profiling of the most promising triazole analogue (compound <b>27a</b>) toward a panel of kinases reveals a high selectivity for CSF1R with respect to its family kinases, but <b>27a</b> also inhibits ABL, SRC, and YES kinases. Molecular docking of <b>27a</b> toward two CSF1R X-ray structures identified two different ligand-inverted binding poses, which triggers interest for further investigations. |
| format | Article |
| id | doaj-art-f3ae3adb5f324bf9aac64c2fd540bee5 |
| institution | Matheson Library |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-f3ae3adb5f324bf9aac64c2fd540bee52025-06-25T14:13:48ZengMDPI AGMolecules1420-30492025-06-013012264110.3390/molecules30122641Evaluating Triazole-Substituted Pyrrolopyrimidines as CSF1R InhibitorsSrinivasulu Cherukupalli0Jan Eickhoff1Carsten Degenhart2Peter Habenberger3Anke Unger4Bård Helge Hoff5Eirik Sundby6Department of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, NO-7491 Trondheim, NorwayLead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227 Dortmund, GermanyLead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227 Dortmund, GermanyLead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227 Dortmund, GermanyLead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227 Dortmund, GermanyDepartment of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, NO-7491 Trondheim, NorwayDepartment of Material Science, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway6-Aryl-7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-4-amines have promising properties as colony-stimulating factor 1 receptor (CSF1R) inhibitors. Inspired by these antagonists, two series of 1,2,3-triazole analogues (28 compounds) were synthesized and evaluated as CSF1R inhibitors. Enzymatic IC<sub>50</sub> profiling showed that 27 of the 28 derivatives had lower IC<sub>50</sub> than the reference drug PLX-3397. Three derivatives displayed CSF1R Ba/F3 cellular IC<sub>50</sub> well below 1 µM. Profiling of the most promising triazole analogue (compound <b>27a</b>) toward a panel of kinases reveals a high selectivity for CSF1R with respect to its family kinases, but <b>27a</b> also inhibits ABL, SRC, and YES kinases. Molecular docking of <b>27a</b> toward two CSF1R X-ray structures identified two different ligand-inverted binding poses, which triggers interest for further investigations.https://www.mdpi.com/1420-3049/30/12/2641CSF1Rtriazolecopper-catalyzed azide–alkyne cycloadditionpyrrolopyrimidine |
| spellingShingle | Srinivasulu Cherukupalli Jan Eickhoff Carsten Degenhart Peter Habenberger Anke Unger Bård Helge Hoff Eirik Sundby Evaluating Triazole-Substituted Pyrrolopyrimidines as CSF1R Inhibitors Molecules CSF1R triazole copper-catalyzed azide–alkyne cycloaddition pyrrolopyrimidine |
| title | Evaluating Triazole-Substituted Pyrrolopyrimidines as CSF1R Inhibitors |
| title_full | Evaluating Triazole-Substituted Pyrrolopyrimidines as CSF1R Inhibitors |
| title_fullStr | Evaluating Triazole-Substituted Pyrrolopyrimidines as CSF1R Inhibitors |
| title_full_unstemmed | Evaluating Triazole-Substituted Pyrrolopyrimidines as CSF1R Inhibitors |
| title_short | Evaluating Triazole-Substituted Pyrrolopyrimidines as CSF1R Inhibitors |
| title_sort | evaluating triazole substituted pyrrolopyrimidines as csf1r inhibitors |
| topic | CSF1R triazole copper-catalyzed azide–alkyne cycloaddition pyrrolopyrimidine |
| url | https://www.mdpi.com/1420-3049/30/12/2641 |
| work_keys_str_mv | AT srinivasulucherukupalli evaluatingtriazolesubstitutedpyrrolopyrimidinesascsf1rinhibitors AT janeickhoff evaluatingtriazolesubstitutedpyrrolopyrimidinesascsf1rinhibitors AT carstendegenhart evaluatingtriazolesubstitutedpyrrolopyrimidinesascsf1rinhibitors AT peterhabenberger evaluatingtriazolesubstitutedpyrrolopyrimidinesascsf1rinhibitors AT ankeunger evaluatingtriazolesubstitutedpyrrolopyrimidinesascsf1rinhibitors AT bardhelgehoff evaluatingtriazolesubstitutedpyrrolopyrimidinesascsf1rinhibitors AT eiriksundby evaluatingtriazolesubstitutedpyrrolopyrimidinesascsf1rinhibitors |