Synthesis and molecular docking simulations of novel azepines based on quinazolinone moiety as prospective antimicrobial and antitumor hedgehog signaling inhibitors.

A series of novel azepine derivatives based on quinazolinone moiety was synthesized through the reaction of quinazolinone chalcones (2a-d) either with 2-amino aniline in acidic medium to give diazepines (3a-d) or with 2-aminophenol to offer oxazepine (4a-d). The structure of the synthesized compounds was confirmed via melting points, elemental analyses, and different spectroscopic techniques. Moreover, these newly compounds mode of action was investigated in-silico using molecular docking against the outer membrane protein A (OMPA), exo-1,3-beta-glucanase for their antimicrobial activity, and against Smoothened (SMO), transcription factor glioma-associated homology (SUFU/GLI-1), the main proteins of Hedgehog signaling pathway to inspect their anticancer potential. Our results showed that, diazepine (3a) and oxazepine (4a) offered the highest binding energy against the target OMPA/ exo-1,3-beta-glucanase proteins and exhibited the potent antimicrobial activities against E. coli, P. aeruginosa, S. aureus, B. subtilis, C. Albicans and A. flavus. As well, diazepine (3a) and oxazepine (4a) achieved the best results among the other compounds, in their binding energy against the target SMO, SUFU/GLI-1 proteins. The in-vitro cytotoxic study was done for them on panel of cancer cell lines HCT-116, HepG2, and MCF-7 and normal cell line WI-38. Conclusively, it was revealed that molecular docking in-silico simulations and the in-vitro experiments were agreed. As a result, our findings elucidated that diazepine (3a) and oxazepine (4a), have the potential to be used as antimicrobial agents and as possible cancer treatment medications.

Hepatoprotective impact of Nigella sativa silver nanocomposite against genotoxicity, oxidative stress, and inflammation induced by thioacetamide.

Protection from liver damage and the repercussion of that harm is thought to be crucial for reducing the number of deaths each year. This work was developed to evaluate the possible role of silver nanocomposite prepared using Nigella sativa (N. sativa) aqueous extract against the hepatic damage brought on by thioacetamide (TAA), with particular attention to how they affect the NF-κß, TNF-α, IL-1ß, and COX-2 signaling pathways. There were seven groups of male Wistar rats used as follows: control, saline, N. sativa aqueous extract (NSAE; 200 mg/kg/d), N. sativa silver nanocomposite (NS-AgNC; 0.25 mg/kg/d), TAA (100 mg/kg; thrice weekly), NSAE + TTA, and NS-AgNC + TAA, respectively. The experiment continued for six weeks. The results showed that NS-AgNPs significantly enhanced liver functions (p<0.05) (albumin, ALP, LDH, AST, total protein, ALT, and globulin) and oxidant/antioxidant biomarkers (p<0.05) (H2O2, MDA, PCC, NO, SOD, CAT, GPx, GR, GST and, GSH), contrasted with TAA group. Moreover, a significant (p<0.05) downregulation of the gene expressions (COX-2, TNF-α, IL-1ß, and NF-κß) was also achieved by using silver nanocomposite therapy. These findings have been supported by histological analysis. Collectively, NS-AgNC exhibits more prominent and well-recognized protective impacts than NSAE in modulating the anti-inflammatory, genotoxicity and oxidative stress effects against TAA-induced liver injuries.

Mechanistic role of quercetin as inhibitor for adenosine deaminase enzyme in rheumatoid arthritis: systematic review.

Rheumatoid arthritis (RA) is an autoimmune disease involving T and B lymphocytes. Autoantibodies contribute to joint deterioration and worsening symptoms. Adenosine deaminase (ADA), an enzyme in purine metabolism, influences adenosine levels and joint inflammation. Inhibiting ADA could impact RA progression. Intracellular ATP breakdown generates adenosine, which increases in hypoxic and inflammatory conditions. Lymphocytes with ADA play a role in RA. Inhibiting lymphocytic ADA activity has an immune-regulatory effect. Synovial fluid levels of ADA are closely associated with the disease's systemic activity, making it a useful parameter for evaluating joint inflammation. Flavonoids, such as quercetin (QUE), are natural substances that can inhibit ADA activity. QUE demonstrates immune-regulatory effects and restores T-cell homeostasis, making it a promising candidate for RA therapy. In this review, we will explore the impact of QUE in suppressing ADA and reducing produced the inflammation in RA, including preclinical investigations and clinical trials.

Simple dihydropyridine-based colorimetric chemosensors for heavy metal ion detection, biological evaluation, molecular docking, and ADMET profiling.

In this study, two novel chemosensors containing dihydropyridine fragment namely; (2E, 2E')-1,1'-(2,6-dimethyl-1,4-dihydropyridine-3,5-diyl)bis(3-(4-(dimethylamino)phenyl)prop-2-en-1-one) (1), (2E,2E',4E,4E')-1,1' -(2,6-dimethyl-1,4-dihydropyridine-3,5-diyl)bis(5-(4-(dimethylamino)phenyl)penta-2,4-dien-1-one) (2) have been synthesized and characterized. The solvatochromic behavior was explored in different solvents of various polarities. The visual detection, as well as UV-Vis and fluorescence measurements were carried out to explore the colorimetric and optical sensing properties of the investigated chemosensors towards various metal ions such as Al3+, Cr3+, Mn2+, Fe3+, Co2+, Ni2+, Cu2+, Mg2+, Hg2+ and Zn2+. The chemosensors 1 and 2 have strong detecting abilities, with excellent sensitivity and selectivity for Cu2+ and Fe3+, respectively, over the other metal ions. The chemosensors were totally reversible upon addition of EDTA to the formed complexes and displayed a turn on-off-on fluorescence response based on an effect of chelation-quenching fluorescence. The antioxidant activities of the investigated chemosensors were assessed. They were examined in-silico for their capacity to block the Akt signaling pathway, which is involved in cancer proliferation with interpreting their pharmacokinetics aspects. Furthermore, in-vitro antitumor evaluation against a panel of cancer cell lines for the investigated chemosensors has been examined. Conclusively, chemosensor 1 was more effective at scavenging free radicals and as an anticancer agent and could be exploited as a therapeutic candidate for cancer therapy than chemosensor 2 due to its potential inhibition of Akt protein.

Enhanced Expression of p53 and Suppression of PI3K/Akt/mTOR by Three Red Sea Algal Extracts: Insights on Their Composition by LC-MS-Based Metabolic Profiling and Molecular Networking.

Brown algae comprise up to 2000 species with wide dissemination in temperate zones. A comprehensive untargeted metabolic profiling guided by molecular networking of three uninvestigated Red-Sea-derived brown algae, namely Sirophysalis trinodis, Polycladia myrica, and Turbinaria triquetra, led to the identification of over 115 metabolites categorized as glycerolipids, fatty acids, sterol lipids, sphingolipids, and phospholipids. The three algae exhibited low-to-moderate antioxidant capacity using DPPH and ABTS assays. Preliminary in vitro antiproliferative studies showed that the algal extracts displayed high cytotoxic activity against a panel of cancer cell lines. The most potent activity was recorded against MCF-7 with IC50 values of 51.37 ± 1.19, 63.44 ± 1.13, and 59.70 ± 1.22 µg/mL for S. trinodis, P. myrica, and T. triquetra, respectively. The cytotoxicity of the algae was selective to MCF-7 without showing notable effects on the proliferation of normal human WISH cells. Morphological studies revealed that the algae caused cell shrinkage, increased cellular debris, triggered detachment, cell rounding, and cytoplasmic condensation in MCF-7 cancer cells. Mechanistic investigations using flow cytometry, qPCR, and Western blot showed that the algae induced apoptosis, initiated cell cycle arrest in the sub-G0/G1 phase, and inhibited the proliferation of cancer cells via increasing mRNA and protein expression of p53, while reducing the expression of PI3K, Akt, and mTOR.

Investigation of novel HCV therapies: Boscia angustifalia & Boscia senegalensis extracts loaded on galactosylated chitosan nanoparticles synthesized by eco-friendly method for HCV treatment.

Hepatitis C virus (HCV) is a major causative agent of chronic liver diseases including chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Treatment of HCV has evolved from early interferon monotherapy to the current all-oral regimens using direct-acting antivirals. However, antiviral resistance has become a critical issue in the treatment of chronic hepatitis C after receiving therapy with direct-acting antivirals (DAA) with a 0.5 % chance of the hepatitis C virus recurrence, similar to other chronic viral infections. So, retreatment options following treatment failure have become crucial issues. Hence, this study aims to investigate a new promising therapy for HCV. In the field of nanomedicine, chitosan nanoparticles are well-known delivery systems that are frequently used as polymeric carriers. Galactosylated chitosan nanoparticles have been widely applied in HCV treatment. In this study, we have modified galactosylation by an eco-friendly method using l-ascorbic instead of hazardous reagents and we have loaded it with newly tested two Boscia extracts each in three different concentrations. The synthesized chitosan nanoparticles showed two dispersion peaks, at 196 ± 29 nm and 1.33 ± 0.36 µm, with a zeta potential of +3.3 ± 0.4mV with high stability in a range of 40.7 mV. The percentage of encapsulation of Boscia angustifalia extract was found to be 46.58 ± 1.33 % and for Boscia senegalensis extract was 9.77 ± 0.33 %. The release of Boscia angustifalia extract from the nanoparticles was about 40 % in acidic media after 180 min and about 60 % in normal pH. However, the release of Boscia senegalensis extract was 20 % in acidic media and 56 % in normal media after 24 h. Testing of these two newly developed composites against HCV was carried out using an in vitro system for the production of hepatitis C virus (HCV) which was established by infection of human hepatoma cells. Evidence for persistent virus production was monitored by the ELISA technique using an anti-HCV-specific antibody. Results obtained showed that all samples had an anti-HCV activity that increased by increasing concentration, and Boscia angustifalia had remarkable anti-HCV activity compared to Boscia senegalensis.

Design, synthesis and molecular docking of novel substituted azepines as inhibitors of PI3K/Akt/TSC2/mTOR signaling pathway in colorectal carcinoma.

A series of novel substituted azepines (2-7) was synthesized using both traditional and ultrasonic techniques. The efficiency of the reaction rate and yield was improved by sonication technique. We identified the newly synthesized compounds based on their melting points, elemental analyses, and spectral data. Human cancers are regulated mainly by the phosphatidylinositol 3-kinase/protein kinases B (PI3K/Akt) pathway, and its abnormal activation is linked to carcinogenesis, and angiogenesis. Using in-silico studies, we evaluated the ability of all the novel substituted diazepines and oxazepines to prevent cancer growth and metastasis by targeting the PI3K/Akt signaling pathway. Based on our findings, compounds 4a and 7a were chosen for in-vitro testing as they ranked via molecular docking the highest binding energies of -10.9, -10.3, -10.6, and -10.4 kcal/mol respectively. Compounds 4a and 7a displayed significant cytotoxicity on Caco-2 colorectal cancer cells with IC50 values of 8.445 ± 2.26 and 33.04 ± 2.06 µM, respectively. Additionally, they considerably suppressed the PI3K/Akt proteins and generated reactive oxygen species (ROS), which increased p53 and Bax, decreased Bcl-2 levels, and arrested the cell cycle at sub-G0/G1 phase. We also observed a remarkable overexpression of the Tuberous Sclerosis Complex 2 (TSC2) gene, an inhibitor of the mammalian target of rapamycin (mTOR). These results showed that compounds 4a and 7a obeyed Lipinski's rule of five and might be potential cancer treatment scaffolds by preventing metastasis and proliferation via blocking the PI3K/Akt/TSC2/m-TOR signaling pathway. This supports our hypothesis that diazepine 4a and oxazepine 7a are promising drug candidates for colorectal cancer.

Synthesis, molecular docking, and in-vitro studies of pyrimidine-2-thione derivatives as antineoplastic agents via potential RAS/PI3K/Akt/JNK inhibition in breast carcinoma cells.

In the present investigation, derivatives from (2-6) containing pyrimidine-2-thione moiety incorporated with different heterocycles such as pyrazoline, phenyl pyrazoline, and pyrimidine were synthesized using different methods. These pyrimidine-2-thione derivatives were evaluated in-silico for their capability to inhibit the H-RAS-GTP active form protein with insight to their pharmacokinetics properties. According to our findings, compound 5a was selected for in vitro studies as it has the in-silico top-ranked binding energy. Furthermore, compound 5a induced apoptosis to panels of cancer cell lines with the best IC50 on MCF-7 breast cancer cells (2.617 ± 1.6 µM). This effect was associated with the inhibition of phosphorylated RAS, JNK proteins, and PI3K/Akt genes expression. Thus, compound 5a has upregulated p21 gene and p53 protein levels. Moreover, 5a arrested the cell cycle progression at the sub-G0/G1 phase. In conclusion, the synthesized compound, 5a exhibited potent antineoplastic activity against breast cancer cell growth by targeting RAS/ PI3K/Akt/ JNK signaling cascades.

Newly Synthesized Pyrazolinone Chalcones as Anticancer Agents via Inhibiting the PI3K/Akt/ERK1/2 Signaling Pathway.

A series of novel pyrazolinone chalcones 3-9 have been synthesized through the condensation of azo pyrazolinone derivatives with various aromatic aldehydes. Spectroscopic techniques and elemental analysis have both corroborated this. Furthermore, all compounds were screened in silico for their ability to inhibit cancer proliferation and metastasis by targeting the PI3K/Akt signaling pathway. This inhibitory pathway might be an efficient approach for the death of cancer cells, angiogenesis, and metastasis prevention. Our results indicated that only compound 6b was the top-ranked. It demonstrated the highest binding energies of -11.1 and -10.7 kcal/mol against the target proteins PI3K and Akt, respectively; thus, it was chosen for in vitro studies. Compound 6b exhibited the most effective cytotoxic impact against the Caco cell line with IC50 of 23.34 ± 0.14 µM. Furthermore, it showed significant inhibition of PI3K/Akt proteins and oxidative stress, leading to elevated Bax and p53 expression, reduced Bcl-2 expression, and triggered cell cycle arrest at the sub-G0/G1 phase. Additionally, it showed significant downregulation of the Raf-1 gene, leading to ERK1/2 protein inhibition. These findings demonstrate that compound 6b obeyed Lipinski's rule of five and might be used as a favored scaffold for cancer treatment by inhibiting proliferation and metastasis via inhibition of the PI3K/Akt and Raf-1/ERK1/2 signaling pathways.

Comparative LC-LTQ-MS-MS Analysis of the Leaf Extracts of Lantana camara and Lantana montevidensis Growing in Egypt with Insights into Their Antioxidant, Anti-Inflammatory, and Cytotoxic Activities.

Lantana camara L. and Lantana montevidensis Briq. (F. Verbenaceae) are invasive ornamental weeds native to the tropical regions of Africa and America. The leaves of both species have been traditionally used as infusions for treating fever, rheumatism, and cancer. LC-MS-MS-guided profiling of the methanolic extracts of the leaves of L. camara and L. montevidensis growing in Egypt led to the putative identification of 59 compounds belonging to terpenoids, flavonoids, iridoid glycosides, phenolic acids, and their derivatives. The in-vitro antioxidants and anti-inflammatory and anticancer activities of the two extracts were investigated. L. camara and L. montevidensis inhibited DPPH• (IC50 = 34.01 ± 1.32 and 47.43 ± 1.74 µg/mL), ABTS+ (IC50 = 30.73 ± 1.42 and 40.37 ± 1.51 µg/mL), and superoxide anion (IC50 = 1.57 ± 0.19 and 1.31 ± 0.14 µg/mL) free radicals. A potent anti-inflammatory effect was observed for both species through the inhibition of elastase release in fMLF/CB-induced human neutrophils (IC50 = 2.40 ± 0.16 and 1.90 ± 0.07 µg/mL). The extracts showed significant cytotoxic activity against a panel of cancer cell lines with the most potent activity against Caco cells (IC50 = 45.65 ± 1.64 and 40.67 ± 1.52 µg/mL for L. camara and L. montevidensis, respectively). Western blotting supported by FACS analysis revealed that the extracts inhibited cancer cell proliferation, reduced metastasis, and induced apoptosis resulting in cell cycle arrest. This was achieved via increasing mRNA and protein expressions of p53 and GSK-3ß as well as decreasing the expression of PI3K, Akt, and cyclin D1.

Chemical compositions of Commiphora opobalsamum stem bark to alleviate liver complications in streptozotocin-induced diabetes in rats: Role of oxidative stress and DNA damage.

CONTEXT: Hyperglycaemia plays an important role in the development of non-alcoholic fatty liver disease, which is a common complication in diabetics. OBJECTIVE: The present study aimed to investigate the chemical composition and the efficacy of Commiphora opobalsamum stem bark butanol fraction in ameliorating liver injury associated with diabetes induced by streptozotocin (STZ) in rats. MATERIALS AND METHODS: The butanol fraction was applied to high-performance liquid chromatography-mass spectrometry (HPLC/MSn) to identify the most bioactive metabolites. Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg body weight), while treatment with the plant extract was performed (100 mg/kg body weight) for three weeks after diabetic induction for one month. RESULTS: Thirty eight metabolites were tentatively identified from the butanol fraction of C. opobalsamum stem bark. Insulin, glutathione, superoxide dismutase, and high density lipoprotein levels in diabetic rats were significantly low (p < 0.05), while glucose, α-amylase, malondialdehyde, aspartate and alanine aminotransferases, cholesterol, triglycerides, low density lipoprotein, tumour necrosis factor-α, interleukin-6, and DNA fragmentation levels were significantly high. Treatment with the plant extract showed improvements in the seleced parameters by variable degrees. Conclusion: The plant extract is considered as a promising natural therapeutic agent against liver injury, hyperglycemia, oxidative stress, inflammation, hyperlipidaemia, and DNA damage.

Quercetin mitigates rheumatoid arthritis by inhibiting adenosine deaminase in rats.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by synovial proliferation and bone destruction. Adenosine deaminase (ADA) is a key inflammatory enzyme that increases joint stiffness and pain in RA. In this study, we evaluated the in-silico, and in vivo inhibitory effect of quercetin isolated from Egyptian Fenugreek on ADA enzyme activity. We also determined the combinatorial effect of quercetin on methotrexate mediated anti-inflammatory efficacy and toxicity. In-silico molecular docking was conducted and confirmed in an in vivo RA rat model. The results showed that the inhibition constant of quercetin on joint ADA by docking and in-vitro was 61.9 and 55.5 mM, respectively. Therefore, quercetin exhibits anti-inflammatory effect in a rat RA model as evidenced by reducing the specific activity of ADA in joint tissues, lower jaw volume, enhance body weight, downregulate ADA gene expression, reduce levels of RA cytokines interleukin-1ß, interleukin-6, tumor necrosis factor-α, also, rheumatoid factor, C-reactive protein, and anti-cyclic citrullinated peptide RA biomarker levels. These findings demonstrate that the purified quercetin has a promising anti-inflammatory effect against RA disease through its inhibitory effects on the ADA enzyme. Furthermore, isolated quercetin improved the anti-inflammatory efficacy of methotrexate, reduced its toxic effects by increasing antioxidant enzymes and reducing oxidative stress.

New Amino Acid Schiff Bases as Anticancer Agents via Potential Mitochondrial Complex I-Associated Hexokinase Inhibition and Targeting AMP-Protein Kinases/mTOR Signaling Pathway.

Two series of novel amino acid Schiff base ligands containing heterocyclic moieties, such as quinazolinone 3-11 and indole 12-20 were successfully synthesized and confirmed by spectroscopic techniques and elemental analysis. Furthermore, all compounds were investigated in silico for their ability to inhibit mitochondrial NADH: ubiquinone oxidoreductase (complex I) by targeting the AMPK/mTOR signaling pathway and inhibiting hexokinase, a key glycolytic enzyme to prevent the Warburg effect in cancer cells. This inhibitory pathway may be an effective strategy to cause cancer cell death due to an insufficient amount of ATP. Our results revealed that, out of 18 compounds, two (11 and 20) were top-ranked as they exhibited the highest binding energies of -8.8, -13.0, -7.9, and -10.0 kcal/mol in the docking analysis, so they were then selected for in vitro assessment. Compound 11 promoted the best cytotoxic effect on MCF-7 with IC50 = 64.05 ± 0.14 µg/mL (0.135 mM) while compound 20 exhibited the best cytotoxic effect on MDA-231 with IC50 = 46.29 ± 0.09 µg/mL (0.166 mM) Compounds 11 and 20 showed significant activation of AMPK protein and oxidative stress, which led to elevated expression of p53 and Bax, reduced Bcl-2 expression, and caused cell cycle arrest at the sub-G0/G1 phase. Moreover, compounds 11 and 20 showed significant inhibition of the mTOR protein, which led to the activation of aerobic glycolysis for survival. This alternative pathway was also blocked as compounds 11 and 20 showed significant inhibitory effects on the hexokinase enzyme. These findings demonstrate that compounds 11 and 20 obeyed Lipinski's rule of five and could be used as privileged scaffolds for cancer therapy via their potential inhibition of mitochondrial complex I-associated hexokinase.

Propolis Potentiates Methotrexate Anticancer Mechanism and Reduces its Toxic Effects.

Egyptian propolis is a powerful antioxidant and free radical scavenger produced by bees. The current study was designed to characterize Egyptian propolis, investigate its anticancer effect in vitro and its protective role against methotrexate (MTX) toxicity in Ehrlich ascites carcinoma (EAC) experimental model. Our results revealed a high content of total phenolics, flavonoids and dihydroflavonols in propolis ethanolic extract (PEE). PEE prompted cytotoxic effects in cancer cell lines and antitumor effects against EAC mice model by reducing tumor volume, count of viable tumor cells with a significant elevation in the life span as well as the mean survival time of mice. The hepatic and renal biochemical and toxicity parameters of EAC-bearing mice treated with MTX were improved by PEE. Also, it elevates the expression of Bax, caspase-3 and cytochrome-C and reduces the Bcl2 expression in EAC cells. Moreover, PEE with MTX induced cell cycle arrest at the G0/G1 phase. Interestingly, the combination of PEE with MTX showed potent apoptosis as shown by DNA fragmentation gel, comet assay and dihydrofolate reductase level (DHFR). These findings demonstrate that Egyptian propolis extract had high chemical diversity and different antioxidant effects. Also, it optimizes the antitumor potential of MTX and declined its toxic effects.