Mohamed Kandeel El-Ashrey

Telomerase is an enzyme that rebuilds chromosomal ends called telomeres, allowing cells to keep dividing.

A new series of pyrazolo[3,4‐ b ]pyridine and spiro‐oxindole derivatives were rationally designed, synthesized, and biologically assessed as either CDK2 or EGFR inhibitors with potential anticancer activity. The CDK2 inhibitory evaluation of pyrazolo[3,4‐ b ]pyridines 6a–g and 7a–f revealed that compounds 6e , 7b , and 7c exhibited potent inhibition (IC₅₀ = 0.88, 1.89, and 1.23 μM, respectively), compared to roscovitine (IC₅₀ = 0.84 μM). Among the spiro‐oxindole derivatives 8a–d , compounds 8b and 8c demonstrated remarkable EGFR inhibition (IC₅₀ = 0.13 and 0.09 μM, respectively) and significant activity against mutant EGFR ^T790M (IC₅₀ = 0.32 and 0.14 μM) relative to gefitinib (IC₅₀ = 0.03 and 0.18 μM, respectively). Furthermore, compounds 6e and 8c exhibited selective cytotoxicity versus MCF‐7 and MDA‐MB231 cancer cells, respectively, with negligible cytotoxic effects on normal Vero cells. Flow cytometric analysis confirmed that compounds 6e and 8c induced G1‐phase cell cycle arrest and apoptosis in MCF‐7 and MDA‐MB‐231, respectively, accompanied by a pronounced increase in the Bax/Bcl‐2 ratio, with values of 12.15 and 16.93 fold, respectively. Molecular docking studies combined with molecular dynamics simulations further supported stable ligand–protein interactions within CDK2, EGFR, and mutant EGFR ^T790M active sites, with favorable binding energies and conformational stability throughout 100 ns trajectories. Collectively, these findings identify compounds 6e and 8c as promising lead scaffolds for further development of CDK2 or EGFR inhibitors with potent and selective anticancer properties.

A new series of benzofuran–pyrazole-based analogues, conjugated with different substituted aromatic and heterocyclic ring systems featuring the pharmacophoric fragments of protein kinase suppressors, 3a–d and 4a–d was synthesized as potential antiproliferative agents. All the new analogues were selected by the NCI to screen their antiproliferative activity against sixty human cancer cell lines (NCI60). The 1H-benzo[d]imidazole derivative 3d demonstrated the highest percentage inhibition for various cancer cell lines and advanced to the five-dose assay. It showed potent anti-proliferative activity against various types of cancer lines with GI₅₀ values ranging from 0.33 to 4.87 μM and LC₅₀ values exceeding 100 μM against the majority of the tested cell lines, confirming its non-lethal effects. Additionally, 3d exhibited multi-targeting PK-suppression activity against B-Raf (V600E), c-Met, Pim-1, EGFR (WT), and VEGFR-2, with IC₅₀ values of 0.078 ± 0.004, 0.405 ± 0.017, 1.053 ± 0.046, 0.177 ± 0.007 and 0.275 ± 0.011 μg mL⁻¹, respectively. Moreover, 3d caused cell cycle arrest at the G0–G1 phase besides early and late apoptosis in MCF-7 cancer cells. In silico molecular docking and ADMET studies were performed on 3d to determine its expected binding interactions with the key regions in the kinase domains, as well as to ascertain its risks of human toxicity, drug-likeness traits, and oral bioavailability.

Background/Objectives: Oxidative stress, the Warburg effect, and resistance to apoptosis are key hallmarks driving colorectal tumorigenesis. This study aimed to develop novel multi-target compounds capable of modulating these pathways. Methods: A library of 24 newly synthesized compounds—incorporating annulated thiophene, thiazole, quinazolinone, 2-oxoindoline, and 1,2,3-oxadiazole scaffolds, as well as N-(1-(4-hydroxy-3-methoxyphenyl)-3-oxo-3-(2-(phenylcarbamothioyl)hydrazineyl) prop-1-en-2-yl)benzamide—was evaluated for antioxidant activity (DPPH assay), PDK-1 and LDHA inhibition, cytotoxic effects against LoVo and HCT-116 colon carcinoma cells, with parallel assessment of safety profiles on normal HUVECs. The underlying anticancer mechanism of the most active compound was investigated through analysis of cell cycle distribution, apoptosis induction, intracellular reactive oxygen species levels, mitochondrial membrane potential disruption, and expression levels of apoptosis-related genes. Molecular docking assessed binding interactions within LDHA and PDK-1 active sites. The physicochemical, drug-likeness, and ADMET properties of the multi-bioactive candidates were predicted in silico. Results: Among the synthesized compounds, thiophenes 3b and 3d exhibited potent PDK-1/LDHA and DPPH/LDHA inhibitions, along with significant cytotoxic effects on LoVo/HCT-116 cells (IC₅₀ in µM: 190.30/170.21 and 156.60/160.96, respectively), while showing minimal cytotoxicity toward HUVECs. Molecular docking revealed favorable interactions with key amino acid residues within the LDHA and/or PDK-1 active sites. Compound 3d notably induced G2/M (LoVo) and G1 (HCT-116) arrest and promoted apoptosis via enhancing ROS generation, modulating Bax/Bcl-2 expressions, disrupting mitochondrial membrane potential, and ultimately activating caspses-3. In silico predictions indicated their promising drug-likeness and pharmacokinetics, though high lipophilicity, poor solubility (especially for 3b), and potential toxicity risks were identified as limitations. Conclusions: Thiophenes 3b and 3d emerged as promising multi-target candidates; however, structural optimization is warranted to enhance their solubility, bioavailability, and safety to support further development as lead anti-colon cancer agents.

Background/Objectives: The alarming rise in antibiotic resistance necessitates the discovery of novel antimicrobial agents. This study aims to design, synthesize, and evaluate new benzofuran–pyrazole-based compounds for their antimicrobial, antioxidant, and anti-inflammatory properties. Methods: New benzofuran–pyrazole hybrid molecules were synthesized using the Vilsmeier–Haach reaction and other chemical processes. The structures of the synthesized compounds were confirmed through micro-analytical and spectral analyses. Their antimicrobial activities were assessed against various bacterial and fungal strains, while antioxidant and anti-inflammatory properties were evaluated using DPPH-free radical scavenging and HRBC membrane stabilization assays, respectively. The most promising compounds were further tested for DNA gyrase B inhibition. Results: Compounds 9, 10, and 11b–d exhibited significant broad-spectrum antimicrobial activity with MIC values ranging from 2.50 to 20 µg/mL. Compounds 4, 6, 9, 11b, and 11d demonstrated high antioxidant activity, with DPPH scavenging percentages between 84.16% and 90.52%. Most compounds showed substantial anti-inflammatory effects, with HRBC membrane stabilization percentages ranging from 86.70% to 99.25%. Compound 9 notably inhibited E. coli DNA gyrase B with an IC50 of 9.80 µM, comparable to ciprofloxacin. Conclusions: The benzofuran–pyrazole-based compounds, particularly compound 9, show great potential as new antimicrobial agents due to their broad-spectrum activity and potent DNA gyrase B inhibition. These findings support further development and optimization of these compounds for clinical applications.

The alarming rise of antibiotic resistance has made it imperative to find novel antimicrobial medications. This study reports the design and synthesis of new molecules based on benzofu-ran-pyrazole scaffolds hybridized with various N/O heterocycles using the molecular hybridiza-tion process. The newly synthesized candidates were confirmed using micro-analytical and spectral analyses, and their antimicrobial characteristics were assessed against different bacterial and fungal isolates in comparison with novobiocin and clotrimazole as antibacterial and anti-fungal standards, respectively. In addition, the new compounds were further evaluated as in vitro antioxidants and anti-inflammatory congeners. The most promising broad spectrum antimicrobial compounds 9, 10 with values ranging from 2.50-20.60 μg/mL were further examined as E. coli DNA gyrase B enzyme suppressors using novobiocin as a reference drug. In silico computational and ADMET studies were carried out for the most active compounds.

Aim: Twenty compounds of 6-nitro-4-substituted quinazolines were synthesized. Materials & methods: The new derivatives were evaluated for their epidermal growth factor receptor (EGFR) inhibitory activity. The most potent derivatives were assessed for their cytotoxicity against colon cancer and lung cancer cells, in addition to normal fibroblast cells. Results & discussion: compound 6c showed a superior to nearly equal cytotoxicity in comparison to gefitinib, it also revealed a good safety profile. Compound 6c caused a cell cycle arrest at G2/M phase in addition to induction of apoptosis. A molecular docking study was conducted on the most active compounds to gain insights of their binding mode in the active site of EGFR enzyme besides ADME prediction of their physicochemical properties and drug likeness profile.

Aim: 22 derivatives of 7-hydroxy-4-methyl-3-substituted benzopyran-2-one were designed, synthesized and evaluated for their anticancer activity. Materials & methods: The prepared compounds were scr...