Design and synthesis of certain 7-Aryl-2-Methyl-3-Substituted Pyrazolo{1,5-a}Pyrimidines as multikinase inhibitors
Copyright © 2023 Elsevier Masson SAS. All rights reserved..
Four new series 7a-e, 8a-e, 9a-e, and 10a-e of 7-aryl-3-substituted pyrazolo[1,5-a]pyrimidines were synthesized and tested for their RTK and STK inhibitory activity. Compound 7d demonstrated potent enzymatic inhibitory activity against TrkA and ALK2 with IC50 0.087and 0.105 μM, respectively, and potent antiproliferative activity against KM12 and EKVX cell lines with IC50 0.82 and 4.13 μM, respectively. Compound 10e showed good enzyme inhibitory activity against TrkA, ALK2, c-KIT, EGFR, PIM1, CK2α, CHK1, and CDK2 in submicromolar values. Additionally 10e revealed antiproliferative activity against MCF7, HCT116 and EKVX with IC50 3.36, 1.40 and 3.49 μM, respectively; with good safety profile. Moreover, 10e showed cell cycle arrest at the G1/S phase and G1 phase in MCF7 and HCT116 cells with good apoptotic effect. Molecular docking studies were fulfilled for compound 10e and illustrated good interaction with the hot spots of the active site of the tested enzymes.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:262 |
|---|---|
| Enthalten in: |
European journal of medicinal chemistry - 262(2023) vom: 15. Dez., Seite 115918 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Al-Qadhi, Mustafa A [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Antineoplastic Agents |
|---|
| Anmerkungen: |
Date Completed 20.11.2023 Date Revised 20.11.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.ejmech.2023.115918 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM36414680X |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM36414680X | ||
| 003 | DE-627 | ||
| 005 | 20231226094827.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.ejmech.2023.115918 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1213.xml |
| 035 | |a (DE-627)NLM36414680X | ||
| 035 | |a (NLM)37922829 | ||
| 035 | |a (PII)S0223-5234(23)00885-1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Al-Qadhi, Mustafa A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Design and synthesis of certain 7-Aryl-2-Methyl-3-Substituted Pyrazolo{1,5-a}Pyrimidines as multikinase inhibitors |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 20.11.2023 | ||
| 500 | |a Date Revised 20.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a Four new series 7a-e, 8a-e, 9a-e, and 10a-e of 7-aryl-3-substituted pyrazolo[1,5-a]pyrimidines were synthesized and tested for their RTK and STK inhibitory activity. Compound 7d demonstrated potent enzymatic inhibitory activity against TrkA and ALK2 with IC50 0.087and 0.105 μM, respectively, and potent antiproliferative activity against KM12 and EKVX cell lines with IC50 0.82 and 4.13 μM, respectively. Compound 10e showed good enzyme inhibitory activity against TrkA, ALK2, c-KIT, EGFR, PIM1, CK2α, CHK1, and CDK2 in submicromolar values. Additionally 10e revealed antiproliferative activity against MCF7, HCT116 and EKVX with IC50 3.36, 1.40 and 3.49 μM, respectively; with good safety profile. Moreover, 10e showed cell cycle arrest at the G1/S phase and G1 phase in MCF7 and HCT116 cells with good apoptotic effect. Molecular docking studies were fulfilled for compound 10e and illustrated good interaction with the hot spots of the active site of the tested enzymes | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Apoptosis | |
| 650 | 4 | |a Cytotoxicity | |
| 650 | 4 | |a Pyrazolo[1,5-a]pyrimidine | |
| 650 | 4 | |a RTKs | |
| 650 | 4 | |a STKs | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Receptor Protein-Tyrosine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 700 | 1 | |a Allam, Heba Abdelrasheed |e verfasserin |4 aut | |
| 700 | 1 | |a Fahim, Samar H |e verfasserin |4 aut | |
| 700 | 1 | |a Yahya, Tawfeek A A |e verfasserin |4 aut | |
| 700 | 1 | |a Ragab, Fatma A F |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t European journal of medicinal chemistry |d 1994 |g 262(2023) vom: 15. Dez., Seite 115918 |w (DE-627)NLM106608835 |x 1768-3254 |7 nnns |
| 773 | 1 | 8 | |g volume:262 |g year:2023 |g day:15 |g month:12 |g pages:115918 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.ejmech.2023.115918 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 262 |j 2023 |b 15 |c 12 |h 115918 | ||