New thiazole/coumarin hybrids as EGFR inhibitors with potential VEGFR-2 inhibition (design, synthesis, biological evaluation, and dynamic stimulation).
- 1Medicinal Chemistry Department, Faculty of Pharmacy, Minia University Minia 61519 Egypt [email protected].
- 2Medicinal Chemistry Department, Faculty of Pharmacy, Minia National University New Minia Egypt.
- 3Department of Pharmacognosy, College of Pharmacy, Almaaqal University 61014 Basrah Iraq.
Abstract
Two new series of coumarin-thiazole hybrids (6a-i and 9a-h) were designed and synthesized as EGFR/VEGFR-2 dual inhibitors. Hybrids 6a-i demonstrated remarkable antiproliferative activities on different NCI-60 cell lines in a single-dose assay. The antiproliferative activities of the newly synthesized hybrids were evaluated against a panel of three human cancer cell lines (HepG2, HCT-116, and MCF-7). Compounds 6a, 6h, 9a, and 9d were the four most active hybrids. Herein, compound 6a was the most active antiproliferative agent among the 6a-i hybrids, with IC50 values ranging from 2.85 µM to 7.66 µM. At the same time, compound 9d was the most active antiproliferative agent among the 9a-h hybrids, with IC50 values ranging from 3.79 µM to 9.80 µM. Furthermore, hybrids 6a, 6h, 9a, and 9d expressed low cytotoxicity for the normal fetal lung WI-38 cells. Consistent with the mechanistic study, the most potent compounds (6a, 6h, and 9d) displayed remarkable inhibitory effectiveness against EGFR and VEGFR-2. Moreover, the most potent hybrid (6a) caused the upregulation of Bax, cytochrome c, and caspase-3 levels and downregulation of Bcl-2 levels. Molecular docking study for compounds 6a, 6h, 9a, and 9d agreed with the mechanistic results. Molecular docking into the ATP-binding site of EGFR (PDB: 1M17 and re-docking RMSD = 1.43 Å) and VEGFR-2 (PDB: 4ASD and re-docking RMSD = 1.67 Å) confirmed strong binding affinities for 6a (ΔG = -10.32 and -9.98 kcal mol-1, respectively) and 9d (ΔG = -10.23 and -9.87 kcal mol-1, respectively), consistent with their enzymatic inhibition profiles. To validate the dynamic stability of binding, 100 ns all-atom molecular dynamics (MD) simulations were performed for 6a and 9d in complex with EGFR, alongside erlotinib and the apo receptor. Compound 6a was carried forward into the 100 ns molecular dynamics simulations of five systems, comprising the apo receptor, the erlotinib complex and the complexes of 6a, 9d, and 9a. Ligand binding compacted the kinase by roughly 2.3 Å in the radius of gyration relative to the apo receptor and reduced Cα fluctuation across the fold. The total protein-ligand interaction energy ranked the four ligands in an order consistent with the enzymatic assay, yielding values of -69.6, -55.6, -50.6 and -41.7 kcal mol-1 for erlotinib, 6a, 9d and 9a against IC50 values of 0.14, 0.27, 0.378, and 2.94 µM, respectively. Furthermore, every pairwise separation exceeded twice the block-averaged standard error. Compound 6a was identified as the lead compound of the series.
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BibTeX
@article{elshemy2026thiazolecoumarin,
title = {{New thiazole/coumarin hybrids as EGFR inhibitors with potential VEGFR-2 inhibition (design, synthesis, biological evaluation, and dynamic stimulation).}},
author = {Sara Waheed Elshemy and Taha F S Ali and Ahmed M Sayed and Samar H Abbas},
journal = {RSC advances},
year = {2026},
month = oct,
doi = {10.1039/d6ra07747a},
url = {https://europepmc.org/article/MED/42953441},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - New thiazole/coumarin hybrids as EGFR inhibitors with potential VEGFR-2 inhibition (design, synthesis, biological evaluation, and dynamic stimulation).
AU - Sara Waheed Elshemy
AU - Taha F S Ali
AU - Ahmed M Sayed
AU - Samar H Abbas
PY - 2026
DA - 2026/10/28
JO - RSC advances
DO - 10.1039/d6ra07747a
UR - https://europepmc.org/article/MED/42953441
AB - Two new series of coumarin-thiazole hybrids (6a-i and 9a-h) were designed and synthesized as EGFR/VEGFR-2 dual inhibitors. Hybrids 6a-i demonstrated remarkable antiproliferative activities on different NCI-60 cell lines in a single-dose assay. The antiproliferative activities of the newly synthesized hybrids were evaluated against a panel of three human cancer cell lines (HepG2, HCT-116, and MCF-7). Compounds 6a, 6h, 9a, and 9d were the four most active hybrids. Herein, compound 6a was the most active antiproliferative agent among the 6a-i hybrids, with IC50 values ranging from 2.85 µM to 7.66 µM. At the same time, compound 9d was the most active antiproliferative agent among the 9a-h hybrids, with IC50 values ranging from 3.79 µM to 9.80 µM. Furthermore, hybrids 6a, 6h, 9a, and 9d expressed low cytotoxicity for the normal fetal lung WI-38 cells. Consistent with the mechanistic study, the most potent compounds (6a, 6h, and 9d) displayed remarkable inhibitory effectiveness against EGFR and VEGFR-2. Moreover, the most potent hybrid (6a) caused the upregulation of Bax, cytochrome c, and caspase-3 levels and downregulation of Bcl-2 levels. Molecular docking study for compounds 6a, 6h, 9a, and 9d agreed with the mechanistic results. Molecular docking into the ATP-binding site of EGFR (PDB: 1M17 and re-docking RMSD = 1.43 Å) and VEGFR-2 (PDB: 4ASD and re-docking RMSD = 1.67 Å) confirmed strong binding affinities for 6a (ΔG = -10.32 and -9.98 kcal mol-1, respectively) and 9d (ΔG = -10.23 and -9.87 kcal mol-1, respectively), consistent with their enzymatic inhibition profiles. To validate the dynamic stability of binding, 100 ns all-atom molecular dynamics (MD) simulations were performed for 6a and 9d in complex with EGFR, alongside erlotinib and the apo receptor. Compound 6a was carried forward into the 100 ns molecular dynamics simulations of five systems, comprising the apo receptor, the erlotinib complex and the complexes of 6a, 9d, and 9a. Ligand binding compacted the kinase by roughly 2.3 Å in the radius of gyration relative to the apo receptor and reduced Cα fluctuation across the fold. The total protein-ligand interaction energy ranked the four ligands in an order consistent with the enzymatic assay, yielding values of -69.6, -55.6, -50.6 and -41.7 kcal mol-1 for erlotinib, 6a, 9d and 9a against IC50 values of 0.14, 0.27, 0.378, and 2.94 µM, respectively. Furthermore, every pairwise separation exceeded twice the block-averaged standard error. Compound 6a was identified as the lead compound of the series.
SN - 2046-2069
ER -