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Synthesis of novel triazoloquinoxaline‐pyrazole hybrids as antiproliferatives, EGFR inhibitors, and apoptosis inducers
Author(s) -
El Saeed Hoda S.,
Bayoumi Ashraf H.,
Sarg Marwa T.,
Ghiaty Adel H.
Publication year - 2020
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.4144
Subject(s) - chemistry , sulforhodamine b , adme , lapatinib , cytotoxicity , gefitinib , pyrazole , apoptosis , cell culture , lead compound , docking (animal) , doxorubicin , biochemistry , stereochemistry , epidermal growth factor receptor , in vitro , cancer , receptor , medicine , nursing , trastuzumab , chemotherapy , biology , breast cancer , genetics , surgery
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.