Browsing by Author "Hany S. Ibrahim"

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Design, synthesis and molecular modeling of new Pyrazolyl-Benzimidazolone hybrids targeting breast Cancer
(Academic Press Inc, 2025-02-15) Mohamed Adardour; Al-Hassan M. Mustafa; Mehdi Oubahmane; Marouane Ait Lahcen; Emad M. Seif; Manal Abdel Fattah Ezzat; Elena Zaballos-García; Joel T. Mague; Ismail Hdoufane; Driss Cherqaoui; Oliver H. Krämer; Wolfgang Sippl; Hany S. Ibrahim; Abdesselam Baouid
Methyl-piperidino-pyrazole (MPP) is a pyrazole derivative acting as a lead estrogen receptor (ER) antagonist and has an anti-breast cancer effect. Since some benzimidazole derivatives were reported for their inhibitory activity against breast cancer, hybrids from these reported compounds (5a-c, 6a-c, 7a-c and 8a-c) were designed to develop anti-breast cancer agents. The synthesis involved 1,3-dipolar cycloaddition of nitrilimines on the benzimidazolone derivatives 2a-b and 3a-b which occurred with chemo- and regioselectivity depending on the dipole and was confirmed by an X-ray structure of 6b. In vitro biological testing of the newly prepared compounds against the 60-cell line panel showed that 5a-c and 6a-c with a partially unsaturated pyrazole ring possessed a high GI% in the T-47D breast cancer cell line with a selectivity margin against different cell lines. Five compounds were selected for apoptotic studies in T-47D cells, of which 6a arrested cells in G1 phase and caused more apoptosis than MPP. The MTT assay revealed that compound 6a has an IC50 = 6.77 ± 0.03 μM against T-47D cells. Furthermore, 6a reduced the estrogen receptor 1 gene expression levels 3-fold in T-47D cells. Molecular dynamics simulations indicated that the complex of the active compound 6a remained stable over the last 150 ns. An analysis of the binding mode revealed that compound 6a exhibited a similar conformation compared to MPP and the co-ligand in the active site of via a specific pose involving noncovalent interactions.
Synthesis of S-alkylated oxadiazole bearing imidazo[2,1-b]thiazole derivatives targeting breast cancer: In vitro cytotoxic evaluation and in vivo radioactive tracing studies
(Academic Press Inc, 2024-11-02) Eman R. Mohammed; Manal Abdel Fattah Ezzat; Emad M. Seif; Basma M. Essa; Hatem A. Abdel-Aziz; Tamer M. Sakr; Hany S. Ibrahim
Breast cancer is the most common invasive cancer diagnosed in women, accounting for most cancer-related fatalities globally. Numerous investigations have revealed that breast cancer is characterized by abnormal expression and maintenance of EGFR levels. In terms of structural study and optimization of several EGFR inhibitors, two series of oxadiazole bearing imidazo[2,1-b]thiazole derivatives were designed and synthesized as potential EGFR inhibitors and assessed for their antitumor activity at NCI-USA. Four derivatives 3b, 3c, 3d and 3e elicited remarkable GI% against MDA-MB-468, T-47D and MCF-7 breast cancer cell lines. Thereafter, MTT assay was performed to reveal that compounds 3b (IC50 = 2.27 µM) and 3d (IC50 = 1.46 µM) showed promising cytotoxic activity against MCF-7 and MDA-MB-468 cell lines, respectively, compared to their reference drugs. Compounds 3b, 3d and 3e revealed good selectivity toward tumor cells with reasonable safety profile when tested against the normal cell line MCF-10a. In vitro EGFR inhibitory assay demonstrated that compounds 3b (IC50 = 0.099 µM) and 3d (IC50 = 0.086 µM) exhibited comparable inhibitory activity to the standard drug erlotinib (IC50 = 0.046 µM). A flow cytometric analysis demonstrated that derivatives 3b and 3d arrested the cell cycle at the S phase in MCF-7 and MDB-MB-468, respectively. Furthermore, the most active derivative 3d was subjected to in vivo radioactive studies. In-vivo biodistribution of 99mTc-3d complex showed a notable elevated accumulation in the targeted sarcoma muscle, indicating the targeting capacity of compound 3d in the tumor of sarcoma mice model. The binding mode of compounds 3b and 3d with EGFR was studied by molecular docking and was further inspected by molecular dynamic simulations. Both compounds were shown to be stable during the course of simulation and demonstrated a plausible interaction pattern with the EGFR binding pocket.