Synthesis and Anti-Breast Cancer Potency of Mono- and Bis-(pyrazolyl[1,2,4]triazolo[3,4‑<i>b</i>][1,3,4]thiadiazine) Derivatives as EGFR/CDK‑2 Target Inhibitors

The target mono- and bis-(6-pyrazolyltriazolo-thiadiazine) derivatives 4a-c and 6a-d were synthesized using a straightforward protocol via reaction of 3-bromoacetylpyrazole 2 with 4-amino-s-triazole-3-thiols 3a-c and bis(4-amino-5-mercapto-s-triazol-3-yl)alkanes 5a-d, respectively. The bis(6-pyrazolyl-s-triazolo[3,4-b][1,3,4]thiadiazine) derivatives 8a,b and 10 were also constructed by reaction of the triazolo[3,4-b][1,3,4]thiadiazine-3-thiol 4c with the proper dibromo compounds 7a,b and 9, respectively. Structures of the new substances were determined by spectroscopic and analytical data. Compounds 4b, 4c, and 6a showed potent cytotoxicity against MCF-7 (IC50 = 3.16, 2.74, and 0.39 μM, respectively) and were safe against the MCF-10A cells. Compounds 4b, 4c, and 6a also showed promising dual EGFR and CDK-2 inhibition activities, particularly 6a was the most effective (IC50 = 19.6 and 87.9 nM, respectively), better than Erlotinib and Roscovitine. Compound 6a treatment induced EGFR and CDK-2 enzyme inhibition by 97.18% and 94.11%, respectively, at 10 μM (the highest concentration). Compound 6a notably induced cell apoptosis in MCF-7 cells, increasing the cell population by total apoptosis 43.3% compared to 1.29% for the untreated control group, increasing the cell population at the S-phase by 39.2% compared to 18.6% (control)

Identification of potential antiviral compounds from Egyptian marine algae against influenza A virus

Influenza is a contagious viral infection of the respiratory tract, affecting nearly 10% of the world’s population, each year. The aim of this study was to extract and identify antiviral compounds against the influenza-A virus (H1N1) from different species of Egyptian marine algae. Three samples of marine macroalgae species were extracted and the antiviral activity of the extracts were tested on Madin Darby Canine Kidney cells. The bioactive compounds present in the most active fractions were identified using gas chromatography-mass spectrometry (GC-MS), then the binding potentials of the identified compounds were examined towards neuraminidase (NA) of the influenza-A virus using molecular docking. The methanolic extract of Sargassum aquifolium showed promising in-vitro antiviral activity with a selectivity index (SI) value of 101. The GC-MS analysis showed twelve compounds and the molecular docking analysis found that tetradecanoic acid showed the strongest binding affinities towards the NA enzyme.</p

DataSheet1_Exploring pyrrolidinyl-spirooxindole natural products as promising platforms for the synthesis of novel spirooxindoles as EGFR/CDK2 inhibitors for halting breast cancer cells.PDF

Cancer represents a global challenge, and the pursuit of developing new cancer treatments that are potent, safe, less prone to drug resistance, and associated with fewer side effects poses a significant challenge in cancer research and drug discovery. Drawing inspiration from pyrrolidinyl-spirooxindole natural products, a novel series of spirooxindoles has been synthesized through a one-pot three-component reaction, involving a [3 + 2] cycloaddition reaction. The cytotoxicity against breast cancer cells (MCF-7 and MDA-MB-231) and safety profile against WISH cells of the newly developed library were assessed using the MTT assay. Compounds 5l and 5o exhibited notable cytotoxicity against MCF-7 cells (IC50 = 3.4 and 4.12 μM, respectively) and MDA-MB-231 cells (IC50 = 8.45 and 4.32 μM, respectively) compared to Erlotinib. Conversely, compounds 5a-f displayed promising cytotoxicity against MCF-7 cells with IC50 values range (IC50 = 5.87–18.5 μM) with selective activity against MDA-MB-231 cancer cells. Compound 5g demonstrated the highest cytotoxicity (IC50 = 2.8 μM) among the tested compounds. Additionally, compounds 5g, 5l, and 5n were found to be safe (non-cytotoxic) against WISH cells with higher IC50 values ranging from 39.33 to 47.2 μM. Compounds 5g, 5l, and 5n underwent testing for their inhibitory effects against EGFR and CDK-2. Remarkably, they demonstrated potent EGFR inhibition, with IC50 values of 0.026, 0.067, and 0.04 μM and inhibition percentages of 92.6%, 89.8%, and 91.2%, respectively, when compared to Erlotinib (IC50 = 0.03 μM, 95.4%). Furthermore, these compounds exhibited potent CDK-2 inhibition, with IC50 values of 0.301, 0.345, and 0.557 μM and inhibition percentages of 91.9%, 89.4%, and 88.7%, respectively, in contrast to Roscovitine (IC50 = 0.556 μM, 92.1%). RT-PCR analysis was performed on both untreated and 5g-treated MCF-7 cells to confirm apoptotic cell death. Treatment with 5g increased the gene expression of pro-apoptotic genes P53, Bax, caspases 3, 8, and 9 with notable fold changes while decreasing the expression of the anti-apoptotic gene Bcl-2. Molecular docking and dynamic simulations (100 ns simulation using AMBER22) were conducted to investigate the binding mode of the most potent candidates, namely, 5g, 5l, and 5n, within the active sites of EGFR and CDK-2.</p

DataSheet2_Exploring pyrrolidinyl-spirooxindole natural products as promising platforms for the synthesis of novel spirooxindoles as EGFR/CDK2 inhibitors for halting breast cancer cells.docx

Cancer represents a global challenge, and the pursuit of developing new cancer treatments that are potent, safe, less prone to drug resistance, and associated with fewer side effects poses a significant challenge in cancer research and drug discovery. Drawing inspiration from pyrrolidinyl-spirooxindole natural products, a novel series of spirooxindoles has been synthesized through a one-pot three-component reaction, involving a [3 + 2] cycloaddition reaction. The cytotoxicity against breast cancer cells (MCF-7 and MDA-MB-231) and safety profile against WISH cells of the newly developed library were assessed using the MTT assay. Compounds 5l and 5o exhibited notable cytotoxicity against MCF-7 cells (IC50 = 3.4 and 4.12 μM, respectively) and MDA-MB-231 cells (IC50 = 8.45 and 4.32 μM, respectively) compared to Erlotinib. Conversely, compounds 5a-f displayed promising cytotoxicity against MCF-7 cells with IC50 values range (IC50 = 5.87–18.5 μM) with selective activity against MDA-MB-231 cancer cells. Compound 5g demonstrated the highest cytotoxicity (IC50 = 2.8 μM) among the tested compounds. Additionally, compounds 5g, 5l, and 5n were found to be safe (non-cytotoxic) against WISH cells with higher IC50 values ranging from 39.33 to 47.2 μM. Compounds 5g, 5l, and 5n underwent testing for their inhibitory effects against EGFR and CDK-2. Remarkably, they demonstrated potent EGFR inhibition, with IC50 values of 0.026, 0.067, and 0.04 μM and inhibition percentages of 92.6%, 89.8%, and 91.2%, respectively, when compared to Erlotinib (IC50 = 0.03 μM, 95.4%). Furthermore, these compounds exhibited potent CDK-2 inhibition, with IC50 values of 0.301, 0.345, and 0.557 μM and inhibition percentages of 91.9%, 89.4%, and 88.7%, respectively, in contrast to Roscovitine (IC50 = 0.556 μM, 92.1%). RT-PCR analysis was performed on both untreated and 5g-treated MCF-7 cells to confirm apoptotic cell death. Treatment with 5g increased the gene expression of pro-apoptotic genes P53, Bax, caspases 3, 8, and 9 with notable fold changes while decreasing the expression of the anti-apoptotic gene Bcl-2. Molecular docking and dynamic simulations (100 ns simulation using AMBER22) were conducted to investigate the binding mode of the most potent candidates, namely, 5g, 5l, and 5n, within the active sites of EGFR and CDK-2.</p

New spiro-indeno[1,2-<i>b</i>]quinoxalines clubbed with benzimidazole scaffold as CDK2 inhibitors for halting non-small cell lung cancer; stereoselective synthesis, molecular dynamics and structural insights

Despite the crucial role of CDK2 in tumorigenesis, few inhibitors reached clinical trials for managing lung cancer, the leading cause of cancer death. Herein, we report combinatorial stereoselective synthesis of rationally designed spiroindeno[1,2-b]quinoxaline-based CDK2 inhibitors for NSCLC therapy. The design relied on merging pharmacophoric motifs and biomimetic scaffold hopping into this privileged skeleton via cost‐effective one-pot multicomponent [3 + 2] cycloaddition reaction. Absolute configuration was assigned by single crystal x-ray diffraction analysis and reaction mechanism was studied by Molecular Electron Density Theory. Initial MTT screening of the series against A549 cells and normal lung fibroblasts Wi-38 elected 6b as the study hit regarding potency (IC50 = 54 nM) and safety (SI = 6.64). In vitro CDK2 inhibition assay revealed that 6b (IC50 = 177 nM) was comparable to roscovitine (IC50 = 141 nM). Docking and molecular dynamic simulations suggested that 6b was stabilised into CDK2 cavity by hydrophobic interactions with key aminoacids.</p

Identification of potential antiviral compounds from Egyptian Red Sea soft corals against Middle East respiratory syndrome coronavirus

The ongoing threat of Middle East respiratory syndrome coronavirus (MERS-CoV) underscores the importance of developing effective antiviral treatments. Current research was conducted to identify potential antiviral compounds from soft corals: Sinularia leptoclados, Sarcophyton ehrenbergi, Nephthea sp., Sarcophyton glaucum and Sarcophyton regulare. The antiviral activities of soft corals extracts were evaluated against MERS-CoV. Gas chromatography-mass spectrometry (GC-MS) was used to identify bioactive compounds. The molecular docking was performed to examine the identified compounds for their binding potentials towards three pathogenic factors of MERS-CoV: main protease, spike and non-structural protein 16/10 complex. The methanolic extract of soft coral Sarcophyton regulare exhibited the most promising activity with 50% inhibitory concentration (IC50) of 4.29 µg/ml and selective index (SI) of 112.2. Among the identified compounds in the active fraction, the molecular docking showed that two fatty acid esters: hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester and octadecanoic acid, 2-hydroxy-1 (hydroxymethyl) ethyl ester had promising docking scores.</p