The current study devised and synthesized a novel class of pyrazole derivatives based on indole as possible inhibitors of cyclin‐dependent kinase‐2 (CDK‐2). 1H NMR, 13C NMR, NOESY, HMQC, and elemental analysis were used to confirm the structural integrity of the synthesized compounds. Promising CDK‐2 inhibitory activity was observed in biological assays, and numerous compounds exhibited sub‐micromolar IC50 values. Compound 5 d outperformed the reference inhibitor Roscovitine (IC50 = 0.716 µM) as the most potent inhibitor (IC50 = 0.536 µM), followed by compound 9 g (IC50 = 0.675 µM). SAR analysis showed that the observed activity was significantly influenced by the electronic nature of the added substituents as well as the orientation of the indole bond, with brominated derivatives exhibiting greater potency. The antiproliferative activity of the most potent compounds against the cancer cell lines HepG2, HCT‐116, and MCF‐7 was further assessed. In addition to having an enhanced selectivity index for normal MCF‐10A cells (SI = 8.00 vs. 4.96 for Roscovitine), compound 5 d had the greatest activity against MCF‐7 cells (IC50 = 6.78 µM), surpassing Roscovitine (IC50 = 8.11 µM). According to mechanistic investigations, compound 5 d significantly reduced the S‐phase population, markedly promoted apoptosis, and caused G1 and G2/M cell‐cycle arrest. Additionally, the consistent binding of compound 5 d within the ATP‐binding pocket of CDK‐2 was confirmed by molecular docking and molecular dynamics simulations, and attractive drug‐like and pharmacokinetic features, similar to those of Roscovitine, were demonstrated by in silico ADMET predictions. All of these results point to compound 5 d as a promising lead scaffold for developing potent CDK‐2‐targeted anticancer agents.
Wagdy M. Eldehna, Zainab M Elsayed, Mohamed R. Elnagar et al.· Drug development research (P...· 0 citations
The development of dual-directed anticancer agents has emerged as an effective strategy to simultaneously modulate tumor proliferation and angiogenesis while overcoming resistance associated with single-target therapies. In the present study, a novel series of benzofuran-based aryl urea derivatives incorporating a 1,3,4-thiadiazole linker were designed as dual VEGFR-2/BRAFWT inhibitors using sorafenib as a pharmacophoric template. The in vitro cytotoxic activity of the synthesized compounds against cervix HeLa, prostate PC-3, colon HCT-116, and breast MCF-7 cancer cell lines was evaluated. Most derivatives showed variable activity, with 5-bromobenzofuran analogues displaying superior potency. Compound 7j emerged as the most active analogue, with IC50 values of 7.83-13.27 μM and reduced toxicity toward normal lung fibroblast WI-38 cells. Enzymatic assays revealed potent dual inhibition of VEGFR-2 and BRAFWT by 7j (IC50 = 0.044 and 0.071 μM, respectively), outperforming sorafenib and vemurafenib. Mechanistic studies showed that 7j induced G2/M cell cycle arrest and promoted apoptosis in HeLa cells. This effect was associated with upregulation of BAX, p53, and caspase-9, downregulation of Bcl-2, and activation of the intrinsic apoptotic pathway. Additionally, in silico studies including molecular docking and molecular dynamics simulations demonstrated stable ligand-target interactions and favorable binding modes of 7j across both VEGFR-2 and BRAF, supporting the proposed hybrid design strategy. Overall, compound 7j represents a promising dual VEGFR-2/BRAFWT inhibitor and highlights benzofuran-based scaffolds as valuable platforms for anticancer drug development.
Marwa I Serag, Mohamed R. Elnagar, Wafaa A. Ewes et al.· Bioorganic & Medicinal Chemi...· 0 citations