The current research employed an animal model of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary gland carcinogenesis. The estrogen receptor-positive human breast adenocarcinoma cell line (MCF-7) was used for in vitro analysis. This was combined with a network pharmacology-based approach to assess the anticancer properties of Spirulina (SP) extract and understand its molecular mechanisms. The results showed that the administration of 1 g/kg of SP increased the antioxidant activity by raising levels of catalase (CAT) and superoxide dismutase (SOD), while decreasing the levels of malonaldehyde (MDA) and protein carbonyl. A histological examination revealed reduced tumor occurrence, decreased estrogen receptor expression, suppressed cell proliferation, and promoted apoptosis in SP protected animals. In addition, SP disrupted the G2/M phase of the MCF-7 cell cycle, inducing apoptosis and reactive oxygen species (ROS) accumulation. It also enhanced intrinsic apoptosis in MCF-7 cells by upregulating cytochrome c, Bax, caspase-8, caspase-9, and caspase-7 proteins, while downregulating Bcl-2 production. The main compounds identified in the LC-MS/MS study of SP were 7-hydroxycoumarin derivatives of cinnamic acid, hinokinin, valeric acid, and α-linolenic acid. These substances specifically targeted three important proteins: ERK1/2 MAPK, PI3K-protein kinase B (AKT), and the epidermal growth factor receptor (EGFR). Network analysis and molecular docking indicated a significant binding affinity between SP and these proteins. This was verified by Western blot analysis that revealed decreased protein levels of p-EGFR, p-ERK1/2, and p-AKT following SP administration. SP was finally reported to suppress MCF-7 cell growth and induce apoptosis by modulating the PI3K/AKT/EGFR and MAPK signaling pathways suggesting EGFR as a potential target of SP in breast cancer (BC) treatment.

Introduction: Epidermal growth factor receptor (EGFR) regulates several cell functions which include cell growth, survival, multiplication, differentiation, and apoptosis. Currently, EGFR kinase inhibitors are of increasing interest as promising targeted antitumor therapeutic agents. Methods: Different thiazolyl-pyrazoline derivatives ( 7a-o) were synthesized and were first tested for anti-proliferative effect towards the A549 lung cancer cell line and the T-47D breast cancer cell line in MTT assay. Thereafter, thiazolyl-pyrazolines ( 7b, 7g, 7l, and 7m) were subsequently evaluated for their PK inhibition for EGFR. Moreover, representative promising derivatives ( 7g and 7m) in cytotoxic and PK inhibition assays were tested to investigate their impact on the apoptosis and cell cycle phases in T-47D cells in order to explore more insights into the antitumor actions of the target thiazolyl-pyrazolines. Furthermore, docking studies were accomplished to evaluate the patterns of binding of thiazolyl-pyrazolines 7b, 7g, 7l, and 7m in the EGFR active pocket (PDB ID: 1M17). Results: Testing the thiazolyl pyrazoline compounds 7a-o on A549 and T-47D cell lines showed IC₅₀ arrays between 3.92 and 89.03 μM, and between 0.75 and 77.10 μM, respectively. Also, the tested thiazolyl-pyrazolines ( 7b, 7g, 7l, and 7m) demonstrated significant sub-micromolar EGFR inhibitory actions with IC₅₀ values 83, 262, 171 and 305 nM, respectively, in comparison to erlotinib (IC₅₀ =57 nM). Discussion: Generally, it was observed that the tested thiazolyl pyrazolines showed more potent antiproliferative activity toward breast cancer cells T-47D than toward lung cancer cell lines A549. In particular, thiazolyl pyrazolines 7g and 7m showed the best activity against A549 cells (IC₅₀ = 3.92 and 6.53 μM) and T-47D cells (IC₅₀ = 0.88 and 0.75 μM). Compounds 7g and 7m provoked a sub-G1 phase arrest and cell apoptosis which are in agreement with the expected outcome of EGFR inhibition. Finally, the molecular docking of 7g and 7m in the active site of EGFR revealed a common binding pattern similar to that of erlotinib which involves the accommodation of the 1,3 thiazol-4-one ring and pyrazoline ring of target compounds in the binding region of erlotinib’s quinazoline ring and anilino moiety.

The SARS-CoV-2 pandemic at the end of 2019 had major worldwide health and economic consequences. Until effective vaccination approaches were created, the healthcare sectors endured a shortage of operative treatments that might prevent the infection’s spread. As a result, academia and the pharmaceutical industry prioritized the development of SARS-CoV2 antiviral medication. Pyranopyrazoles have been shown to play a prominent function in pharmaceutical chemistry and drug sighting because of their significant bioactive properties. We provide herein a novel sequence of pyranopyrazoles and their annulated systems whose antiviral efficacy and cytotoxicity were explored versus human coronavirus 229E (HCoV-229E) Vero-E6 cell lines as a model for the Coronaviridae family. Fifteen synthetic congeners pointed out miscellaneous antiviral efficacies against HCoV-229E with variable inhibition degrees. Compound 18 showed a high selectivity index (SI = 12.6) that established spectacular inhibitory capacity against human coronavirus 229E. Compounds 6, 7, and 14 exposed moderate efficacies. Compounds 6, 7, 14, and 18 exhibited substantial antiviral action through the replication phase with reduction percentages extending from 53.6%, 60.7%, and 55% to 82.2%, correspondingly. Likewise, when assessed to the positive control tipranavir (88.6%), the inhibitory efficiency of compounds 6, 7, 14, and 18 versus the SARS-CoV2 Mpro provided high percentages of 80.4%, 73.1%, 81.4% and up to 84.5%, respectively. In silico studies were performed to investigate further the biological activity and the target compounds’ physical and chemical features, including molecular dynamic (MD) simulations, protein–ligand docking, ADME studies, and density functional theory (DFT) calculations. These inquiries demonstrated that this series of metabolically stable pyranopyrazoles and their annulated systems are effective human coronavirus inhibitors that inhibit the viral M^pro protein and may have emerged as a novel COVID-19 curative option.

We describe the design and synthesis of two isatin-tethered quinolines series (Q6a–h and Q8a–h), in connection with our research interest in developing novel isatin-bearing anti-tubercular candidates. In a previous study, a series of small molecules bearing a quinoline-3-carbohydrazone moiety was developed as anti-tubercular agents, and compound IV disclosed the highest potency with MIC value equal to 6.24 µg/mL. In the current work, we adopted the bioisosteric replacement approach to replace the 3,4,5-trimethoxy-benzylidene moiety in the lead compound IV with the isatin motif, a privileged scaffold in the TB drug discovery, to furnish the first series of target molecules Q6a–h. Thereafter, the isatin motif was N-substituted with either a methyl or benzyl group to furnish the second series Q8a–h. All of the designed quinoilne-isatin conjugates Q6a–h and Q8a–h were synthesized and then biologically assessed for anti-tubercular actions towards drug-susceptible, MDR, and XDR strains. Superiorly, the N-benzyl-bearing compound Q8b possessed the best activities against the examined M. tuberculosis strains with MICs equal 0.06, 0.24, and 1.95 µg/mL, respectively.

Objective: This study aims to develop an intranasal (IN) delivery system for glioblastoma multiforme (GBM) management using repurposed superparamagnetic iron-oxide (SPION) loaded with atorvastatin (ATO)-nanostructured lipid carrier (NLC). Methods: Emulsification and ultrasonication were used to formulate ATO-NLCs, and the best formula was loaded with SPION to make the final atorvastatin/superparamagnetic iron oxide-loaded nanostructured lipid carrier (ASN) formulation. Entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), and drug release after 6 h (Q6h) were evaluated for NLCs. ASN was tested for cytotoxicity on T98G cancer cells, and the cell cycle was examined to determine cell death. Furthermore, the ability of the optimal formulation to suppress the levels of inflammatory biomarkers was investigated in Lipopolysaccharide (LPS)-induced inflammation. The brain-targeting behavior of IN-ASN was visualized in rabbits via confocal laser scanning microscopy (CLSM). Results: The optimum NLC exhibited a spherical shape, EE% of 84.0 ± 0.67%, PS of 282.50 ± 0.51 nm, ZP of −18.40 ± 0.15 mV, and Q6h of 89.23%. The cytotoxicity of ASN against cancer cells was 4.4-fold higher than ATO suspension, with a 1.3-fold increment in cell apoptosis. ASN showed significantly reduced pro-inflammatory biomarkers (IL-β, IL-6, TNF-α, TLR4, NF-қB), whereas CLSM revealed enhanced brain delivery with no observed histopathological nasal irritation. The in silico analysis demonstrated enhanced ATO-ADME (absorption, distribution, metabolism, and excretion) properties, while the network pharmacology study identified 10 target GBM genes, among which MAPK3 was the most prominent with a good binding score as elucidated by the simulated docking study. Conclusions: These findings may present ATO/SPION-NLCs as significant evidence for repurposing atorvastatin in the treatment of glioblastoma multiforme.