Synthesis and antitumor property of triazole-aryloxyacetyl hydrazide hybrids with furo[2,3-d]pyrimidine scaffold
摘要
This study describes the design and synthesis of a novel series of triazole-aryloxyacetyl hydrazide hybrids with furo[2,3-d]pyrimidine scaffold. The structure elucidations were performed using 1 H NMR, 13 C NMR and high-resolution mass spectrometry (HR-MS). The in vitro antitumor activities evaluation indicated that several derivatives exhibited considerable inhibiting effect against HepG2 cell lines, with IC50 values ranging from 4.82 to 69.83 µmol/L for compounds 5a–5l, 18.37 to > 100 µmol/L for compounds 6a–6j, 11.21 and 6.07 µmol/L for compounds 7a and 7b, respectively. Among them, compounds 5d and 5e appeared the most potent activity, along with notably lower cytotoxicity against the normal human liver cell line and the selectivity indices (SIs) were calculated to be 3.36 and 3.02, respectively, underscoring their antitumor potential. Furthermore, compound 5d not only induced concentration-dependent apoptosis but also effectively suppressed HepG2 cell migration. Following molecular docking studies demonstrated that compound 5d interacts with EGFR in a manner similar to gefitinib, suggesting its potential as an EGFR inhibitor. Preliminary comparative structure-activity relationship revealed that the bicyclic furo[2,3-d]pyrimidine core bearing a C-4 aryloxyacetyl hydrazide moiety was crucial for high activity, outperforming the tricyclic triazole-containing analogs (6a–6j). In addition, the introduction of halogen substituents (F, Cl) at the R1 position enhanced potency, as evidenced by compounds 5d, 5e, and 7b. Conversely, the tricyclic series (6a–6j) showed diminished activity. A comparison with the potent compounds 7a and 7b suggests that this may be due to unfavorable steric effects. This insight provides a direction for subsequent molecular optimization efforts.