Design and synthesis of certain 7-Aryl-2-Methyl-3-Substituted Pyrazolo{1,5-a}Pyrimidines as multikinase inhibitors

Mustafa A Al-Qadhi; Heba Abdelrasheed Allam; Samar H Fahim; Tawfeek A A Yahya; Fatma A F Ragab

doi:10.1016/j.ejmech.2023.115918

Design and synthesis of certain 7-Aryl-2-Methyl-3-Substituted Pyrazolo{1,5-a}Pyrimidines as multikinase inhibitors

Eur J Med Chem. 2023 Dec 15:262:115918. doi: 10.1016/j.ejmech.2023.115918. Epub 2023 Oct 29.

Authors

Mustafa A Al-Qadhi¹, Heba Abdelrasheed Allam², Samar H Fahim³, Tawfeek A A Yahya¹, Fatma A F Ragab³

Affiliations

¹ Department of Medicinal Chemistry, Faculty of Pharmacy, Sana'a University, P.O. Box, 18084, Sana'a, Yemen.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box, 11562, Egypt. Electronic address: Heba.abdelkhalek@pharma.cu.edu.eg.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box, 11562, Egypt.

PMID: 37922829
DOI: 10.1016/j.ejmech.2023.115918

Abstract

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.

Keywords: Apoptosis; Cytotoxicity; Pyrazolo[1,5-a]pyrimidine; RTKs; STKs.

MeSH terms

Antineoplastic Agents* / chemistry
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemistry
Pyrimidines / chemistry
Receptor Protein-Tyrosine Kinases
Structure-Activity Relationship

Substances

Antineoplastic Agents
Pyrimidines
Protein Kinase Inhibitors
Receptor Protein-Tyrosine Kinases