Authors
Mohammed N Sallam, Ahmed A Al-Karmalawy, Eslam M Abbass, Samia S Hawas, Abeer M El-Naggar, A M A Hassan
Published in
RSC advances. Volume 15. Issue 47. Pages 40078-40092. Oct 20, 2025. Epub Oct 22, 2025.
Abstract
A new series of pyrazole-thiophene hybrid derivatives was rationally designed, synthesized, and biologically evaluated for anticancer potential. Cytotoxicity screening toward MCF-7 and HepG2 cell lines identified 2 as the most potent analogue (IC50 = 6.57 μM, MCF-7; 8.86 μM, HepG2), with activity comparable to the reference drugs doxorubicin, erlotinib, and sorafenib. Selectivity toward MCF-7 was observed for 8 (IC50 = 8.08 μM), while 14 displayed moderate dual activity (IC50 = 12.94 μM, MCF-7; 19.59 μM, HepG2). Enzyme inhibition assays revealed that 2 effectively suppressed wild-type EGFR (IC50 = 16.25 μg mL-1) and the clinically relevant T790M mutant (17.8 μg mL-1), whereas 14 showed balanced dual inhibition (16.33 and 16.6 μg mL-1, respectively). Notably, 8 emerged as the most active VEGFR-2 inhibitor (35.85 μg mL-1), significantly outperforming 14 (112.36 μg mL-1) and 2 (242.94 μg mL-1). Mechanistic studies demonstrated that 14 brought MCF-7 cells in the G0/G1 phase to cell-cycle arrest (74.16% vs. 55.31% in control), increased the apoptotic population to 26.32%, and caused minimal necrosis (4.2%). Molecular docking supported these findings, revealing strong binding affinities and favorable interactions of 2, 14, and 8 with EGFR (wild-type and T790M mutant) and VEGFR-2, respectively. Taken together, these results highlight 2, 8, and 14 as promising pyrazole-thiophene multitargeted anticancer leads, offering potential for further optimization to overcome kinase-driven resistance in cancer therapy.
PMID:
41133127
Bibliographic data and abstract were imported from PubMed on 24 Oct 2025.
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