Synthesis of novel triazoloquinoxaline‐pyrazole hybrids as antiproliferatives, EGFR inhibitors, and apoptosis inducers

Abstract

Novel triazoloquinoxaline-pyrazole hybrids have been developed and synthesized. All derivatives' anticancer activity has been evaluated using Sulforhodamine-B (SRB) assay for cancer cell lines MCF-7, HepG-2, and HCT-116. Compound 12b was 2-fold more cytotoxic than Doxorubicin, while 12a,c demonstrated comparable cytotoxicity to the reference Doxorubicin. Further investigations on the most active derivatives 12a-c were done to study their inhibitory activity on two EGFR subtypes wild EGFR and mutant EGFR (L858R) tyrosine kinases in MCF-7 cell lines. Compound 12b exhibited potent inhibitory activity toward wild EGFR (IC 50 : 0.98 μM) when compared to Gefitinib (IC 50 :18.07 μM). 12b also possessed a marked inhibition against mutant EGFR (L858R-TK) exhibiting (IC 50 :27.45 μM) in comparison to Lapatinib (IC 50 : 61.06 μM). Compound 12b improved the active Caspase-3 value and the BAX/Bcl-2 reference. Furthermore, 12b showed G2/M cell cycle arrest induced apoptosis in cell line MCF-7. In addition, the most active derivatives have been orally bioavailable as shown in the in silico determination of the ADME characters. The binding pattern of compound 12b was also studied by molecular docking.

Nitrogen‐Containing Heterocyclic Scaffolds as EGFR Inhibitors: Design Approaches, Molecular Docking, and Structure‐Activity Relationships

“…Additionally, docking studies was also carried out on an EGFR active site, 39 a had similar binding energy to the reference compound, erlotinib (scores of 6.28 and 5.35 Kcal/mol). [109] Sayed and co-worker in 2019 synthesized the thiazolylpyrazole scaffold as anticancer agents. the series of motifs were tested against HepG-2 for antiproliferative potential.…”

“…According to flow cytometry and cell cycle analysis, 39 b was able to induce apoptosis in MCF‐7 cells, halt the cell cycle in the G2/M phase, and boost the expression of caspase‐3 and BAX/Bcl‐2 ratios using annexin V‐FITC staining. Additionally, docking studies was also carried out on an EGFR active site, 39 a had similar binding energy to the reference compound, erlotinib (scores of 6.28 and 5.35 Kcal/mol) [109] …”