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Sammar Fathy Elhabal,1 Saeed AS Al-Zuhairy,2 Mohamed El-Nabarawi,3 Mohamed Fathi Mohamed Elrefai,4,5 Mai S Shoela,6 Sandra Hababeh,7 Jakline Nelson,8 Mohamed A Abdel Khalek,9 Marwa Fady,10,11 Nahla A Elzohairy,11,12 Mariam E Amin,13 Gehad M Khamis,6 Amira Rizk,14 Sara Mohamed Ahmed,15 Ahmed A El-Rashedy,16 Mohamed Mohany,17 Abdulaziz S Al-Roujayee,18 Ahmed Mohsen Faheem,19 Amr Amin20 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Mokattam, Cairo, Egypt; 2Department of Pharmacy, Kut University College, Kut, Wasit, Iraq; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 4Department of Anatomy, physiology and Biochemistry, Faculty of Medicine, the Hashemite University, Zarqa, Jordan; 5Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 6Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 7Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; 8Department of Microbiology and Immunology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt; 9Institute of Nanoscience and Nanotechnology, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt; 10Zagazig University Hospitals, Infection Control Unit, Zagazig, 44519, Egypt; 11Modern University for Technology & Information, Department of Microbiology and Immunology, Pharmacy College., Cairo Governorat, Egypt; 12Air Force Specialized Hospital, Cairo, Egypt; 13Microbiology and Immunology Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt; 14Food Science and technology, Department Faculty of Agricultural, Tanta University, Tanta, Egypt; 15Department of Pharmaceutics, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza, 12585, Egypt; 16Chemistry of Natural and Microbial Products Department, National Research Center (NRC), Giza, Egypt; 17Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; 18Department of Dermatology and Venereology, College of Medicine, Al Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia; 19Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; 20College of Medicine, Sharjah University, Sharjah, United Arab EmiratesCorrespondence: Sammar Fathy Elhabal; Amr Amin, Email sammar_fathy2007@yahoo.com, sammar.fathy@pharm.mti.edu.eg; a.amin@sharjah.ac.aeBackground: Diabetic foot ulcers present a formidable challenge due to colonization by biofilm-forming microorganisms, heightened oxidative stress, and continuous wound maceration caused by excessive exudation.Methods: To address these issues, we developed a robust, stretchable, electro-conductive, self-healing, antioxidant, and antibiofilm hydrogel. This hydrogel was synthesized through the crosslinking of polyvinyl alcohol (PVA) and chitosan (CH) with boric acid. To enhance its antimicrobial efficacy, graphene oxide (GO), produced via electrochemical exfoliation in a zinc ion-based electrolyte medium, was incorporated. For optimal antibiofilm performance, GO was functionalized with cranberry (CR) phenolic extracts, forming a graphene oxide-cranberry nanohybrid (GO-CR).Results: The incorporation of GO-CR into the hydrogel significantly improved its stretchability (280% for PVA/CH/GO-CR compared to 200% for PVA/CH). Additionally, the hydrogel demonstrated efficient photothermal conversion under near-infrared (NIR) light, enabling dynamic exudate removal, which is expected to minimize retained exudate between the wound and the dressing, reducing the risk of wound maceration. The hydrogel effectively reduced levels of lipopolysaccharide (LPS)-induced skin inflammation markers, significantly lowering the expression of NLRP3, TNF-α, IL-6, and IL-1β by 39.2%, 31.9%, 41%, and 52.3%, respectively. Histopathological and immunohistochemical analyses further confirmed reduced inflammation and enhanced wound healing.Conclusion: The PVA/CH/GO-CR hydrogel exhibits multifunctional properties that enhance wound healing ulcers. Its superior mechanical, antibacterial, and anti-inflammatory properties and ability to promote angiogenesis make it a promising candidate for effective wound management in diabetic patients. Keywords: antibiofilm, cranberry extract, electro conductive hydrogel, graphene oxide, nanocomposite, photothermal conversion, self-healing, wound healing

Sammar Fathy ELhabal,1 Hanan Mohamed Elwy,2 Soha Hassanin,3 Ahmed A El-Rashedy,4 Alaaeldin Ahmed Hamza,5 Mohammad Ahmad Khasawneh6 1Department of Pharmaceutics and Industrial Pharmacy, Modern University for Technology and Information, Cairo, Egypt; 2Pharmaceutical Chemistry Department, National Organization for Drug Control and Research, Cairo, Egypt; 3Biochemistry Department, Modern University for Technology and information, Cairo, Egypt; 4Chemistry of Natural and Microbial Products Department, National Research Center (NRC), Giza, Egypt; 5Biology Department, National Organization for Drug Control and Research, Giza, Egypt; 6Department of Chemistry, United Arab Emirates University, Al-Ain, United Arab EmiratesCorrespondence: Mohammad Ahmad Khasawneh; Alaaeldin Ahmed Hamza, Email mohammad.khasawneh@uaeu.ac.ae; alaa17mm@gmail.comIntroduction: Metal nanoparticle synthesis using plant has emerged as an eco-friendly, clean, and viable strategy alternative to chemical and physical approaches.Methods: The fruit extract of Salvadora persica (SP) was utilized as a reducing and stabilizing agent in the synthesis of gold (AuNPs) and copper (CuNPs) nanoparticles.Results: UV–Vis spectra of the AuNPs and CuNPs showed peaks at the wavelengths of 530 nm and 440 nm, respectively. Transmission electron microscopy showed that nanoparticles exhibited a mainly spherical form, with a distribution range of 100 to 113 nm in diameter for AuNPs and of 130 to 135 nm in diameter for CuNPs. While energy-dispersive X-ray spectroscopy was able to confirm the existence of AuNPs and CuNPs. The alcoholic extract of the fruit SP was analyzed by GC-MS in order to identify whether or not it contained any active phytochemicals. Fourier-transform infrared spectra confirmed the presence capping functional biomolecules of SP on the surface of nanoparticles that acts as stabilizers. Analysis of the zeta potential revealed that NPs with high degree of stability, as demonstrated by a strong negative potential value in the range of 25.2 to 28.7 mV. Results showed that both green AuNPs and CuNPs have potential antimicrobial activity against human pathogens such gram-negative bacteria and gram-positive bacteria, with CuNPs having antimicrobial activity higher than AuNPs. In addition, AuNPs and CuNPs have promising antioxidant and anticancer properties when applied to MCF-7 and MDA-MB-231 breast cancer cells. Studies of molecular docking of SP bioactive compounds were conducted against methenyl tetrahydrofolate synthetase. Among all of them, Beta – Sitosterol was the most prominent.Conclusion: These AuNPs and CuNPs are particularly appealing in a variety of applications in the pharmaceutical and medicinal industries due to their economical and environmentally friendly production.Keywords: Salvadora persica, green nanoparticles, antioxidant, antibacterial, anticancer

The COVID-19 pandemic has caused significant mortality and morbidity for millions of people. Severe Acute Respiratory Syndrome-2 (SARS-CoV-2) virus is capable of causing severe and fatal diseases. We evaluated the antiviral properties of Aspergillus tamarii SP73-EGY isolate extract against low pathogenic coronavirus (229E), Adeno-7- and Herpes-2 viruses. The extract showed a high selectivity index (SI = 43.4) and a significant inhibition of 229E (IC 50  = 8.205 μg/ml). It was stronger than the drug control, remdesivir (IC 50  = 38.2 μg/ml, SI = 7.29). However, the extract showed minimal efficacy against Adeno-7- and Herpes-2-Viruses (IC 50  = 22.52, 47.79 μg/ml, and SI = 6.75, 5.08, respectively). It exhibited profound efficacy against the highly pathogenic SARS-CoV-2 (IC 50  = 8.306 μg/ml, SI = 42.2). Kojic acid, the primary component of the extract, showed substantial antiviral activity against SARS-CoV-2 (IC 50  = 23.4 μg/ml, SI = 5.6), Remdesivir (IC 50  = 4.55 μg/ml, SI = 61.45). Therefore, the extract demonstrated the most notable antiviral characteristics against coronavirus infection. Co-infecting microorganisms may contribute to immune system deterioration and airway injury caused by SARS-CoV-2. The extract showed significant efficacy against E. coli and P. aeruginosa, with an inhibition range of 3.5-10 mm at a concentration of 200 mg/ml. A molecular docking study showed that hexadecanoic, Kojic, octanoic acids, and 4(4-Methylbenzylidene)cyclohexane-1,3-dione have stronger binding affinity to the SARS-CoV-2 M pro than Remdesivir. Molecular dynamics simulations were employed to examine the structural stability and flexibility of these complexes. This confirmed the high binding affinities of Kojic acid and 4(4-Methylbenzylidene)cyclohexane-1,3-dione, thereby proving their potential as novel anti-SARS-CoV-2., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Molecular hybridization of substituted 2-phenylbenzimidazole and pyridine moieties afforded a new series of antimalarial targeting compounds 5a-l. They were assessed against both chloroquine resistant -W2 (CR-W2) and chloroquine sensitive-D6 (CS-D6) strains of P. falciparum. Artemisinin and chloroquine were used as standards drugs. Results revealed that compounds 5e, 5j, 5k and 5l were the most effective against CS-D6 P. falciparum strain with IC 50 values ranged between 0.019 and 0.056 µM and selectivity index values of 7551.95-13642.10. In addition to 5j and 5k derivatives, another four tested compounds 5c, 5d, 5f and 5g exerted effective antimalarial activity against CR-W2 strain of P. falciparum, their IC 50 values were between 0.046 and 0.253 µM with high selectivity index values ranged from 2610.23 to 1024.50. Upon assessing DHFR inhibitory activity of the energetic derivatives, compounds 5j, 5k, and 5e exhibited IC 50 values of 0.72, 3.95, and 5.31 µM, respectively, in comparison to the reference medication trimethoprim, which has an IC 50 of 13.36 µM. Moreover, molecular dynamic simulations and docking experiments were applied to the most active derivative, 5j, into the catalytic binding site of wild-PfDHFR-TS, were done and showed interesting binding profiles and affinities. Furthermore, in silico physicochemical and pharmacokinetic parameters were predicted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Limonoids are important constituents of citrus that have a significant impact on promoting human health. Therefore, the primary focus of this research was to assess the overall limonoid content and isolate limonoids from Adalia lemon (Citrus limon L.) peels for their potential use as antioxidants and anti-diabetic agents. The levels of limonoid aglycones in the C. limon peel extract were quantified through a colorimetric assay, revealing a concentration of 16.53 ± 0.93 mg/L limonin equivalent. Furthermore, the total concentration of limonoid glucosides was determined to be 54.38 ± 1.02 mg/L. The study successfully identified five isolated limonoids, namely limonin, deacetylnomilin, nomilin, obacunone 17-O-β-D-glucopyranoside, and limonin 17-O-β-D-glucopyranoside, along with their respective yields. The efficacy of the limonoids-rich extract and the five isolated compounds was evaluated at three different concentrations (50, 100, and 200 µg/mL). It was found that both obacunone 17-O-β-D-glucopyranoside and limonin 17-O-β-D-glucopyranoside possessed the highest antioxidant, free radical scavenging, and anti-diabetic activities, followed by deacetylnomilin, and then the limonoids-rich extract. The molecular dynamic simulations were conducted to predict the behavior of the isolated compounds upon binding to the protein's active site, as well as their interaction and stability. The results revealed that limonin 17-O-β-D-glucopyranoside bound to the protein complex system exhibited a relatively more stable conformation than the Apo system. The analysis of Solvent Accessible Surface Area (SASA), in conjunction with the data obtained from Root-Mean-Square Deviation (RMSD), Root-Mean-Square Fluctuation (RMSF), and Radius of Gyration (ROG) computations, provided further evidence that the limonin 17-O-β-D-glucopyranoside complex system remained stable within the catalytic domain binding site of the human pancreatic alpha-amylase (HPA)-receptor. The research findings suggest that the limonoids found in Adalia lemon peels have the potential to be used as effective natural substances in creating innovative therapeutic treatments for conditions related to oxidative stress and disorders in carbohydrate metabolism., (© 2024. The Author(s).)

Using plant extracts as photosensitizers in photodynamic therapy (PDT) represents a significant green approach toward sustainability. This study investigates beetroot juice (BRJ), betanin, and their liposomal formulations (Lip-BRJ, Lip-Bet) as photosensitizers in cancer PDT. BRJ was prepared, and its betanin content was quantified via HPLC. The p-nitrosodimethylaniline (RNO)/imidazole technique monitored the singlet oxygen formation. BRJ and betanin decreased the RNO absorbance at 440 nm by 12% and 9% after 45 min of irradiation, respectively. Furthermore, betanin interaction with Bcl-2 proteins was examined using binding free energy analysis and molecular dynamic simulation. The results revealed favorable interactions with ΔG values of -40.94 kcal/mol. Then, BRJ, betanin, Lip-BRJ, and Lip-Bet were tested as photosensitizers on normal (HEK 293) and human lung cancer (A549) cell lines. Irradiation significantly enhanced the cytotoxicity of Lip-Bet on HEK 293 cells (20% cell viability at 2000 µg/mL) and A549 cells (13% cell viability at 1000 µg/mL). For Lip-BRJ, irradiation significantly enhanced the cytotoxicity on HEK 293 cells at lower concentrations and on A549 cells at all tested concentrations. These results proved the positive effect of light and liposomal encapsulation on the anticancer activity of betanin and BRJ, suggesting the efficiency of liposomal beetroot pigments as green photosensitizers.

Sustained inflammatory responses can badly affect several vital organs and lead to chronic inflammation-related disorders, such as atherosclerosis, pneumonia, rheumatoid arthritis, obesity, diabetes, Alzheimer's disease, and cancers. Salvia multicaulis is one of the widely distributed plants that contains several biologically active phytochemicals and diterpenoids with anti-inflammatory effects. Therefore, finding alternative and safer natural plant-extracted compounds with good curative anti-inflammatory efficiencies is an urgent need for the clinical treatment of inflammation-related diseases. In the current study, S. multicaulis Vahl was used to extract and isolate two compounds identified as salvimulticanol and candesalvone B methyl ester to examine their effects against inflammation in murine macrophage RAW264.7 cells that were induced by lipopolysaccharide (LPS). Accordingly, after culturing RAW264.7 cells and induction of inflammation by LPS (100 ng/ml), cells were exposed to different concentrations (9, 18, 37.5, 75, and 150 µM) of each compound. Then, Griess assay for detection of nitric oxide (NO) levels and western blotting for the determination of inducible nitric oxide synthase (iNOS) expression were performed. Molecular docking and molecular dynamics (MD) simulation studies were employed to investigate the anti-inflammatory mechanism. Our obtained results validated that the level of NO was significantly decreased in the macrophage cell suspensions as a response to salvimulticanol treatment in a dose-dependent manner (IC 50 : 25.1 ± 1.2 µM) as compared to the methyl ester of candesalvone B which exerted a weaker inhibition (IC 50 : 69.2 ± 3.0 µM). This decline in NO percentage was comparable with a down-regulation of iNOS expression by western blotting. Salvimulticanol strongly interacted with both the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) complex and the inhibitor of nuclear factor kappa-B (NF- κ B) kinase subunit beta (IKKβ) to disrupt their inflammatory activation due to the significant hydrogen bonds and effective interactions with amino acid residues present in the target proteins' active sites. S.multicaulis is a rich natural source of the aromatic abietane diterpenoid, salvimulticanol, which exerted a strong anti-inflammatory effect through targeting iNOS and diminishing NO production in LPS-induced RAW264.7 cells in a mechanism that is dependent on the inhibition of TLR4-MD-2 and IKKβ as activators of the classical NF- κ B-mediated inflammatory pathway., Competing Interests: Conflict of interestThe authors declared no conflict of interest., (© King Abdulaziz City for Science and Technology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

In the present study, numerous acridine derivatives A1-A20 were synthesized via aromatic nucleophilic substitution (S NAr ) reaction of 9-chloroacridine with carbonyl hydrazides, amines, or phenolic derivatives depending upon facile, novel, and eco-friendly approaches (Microwave and ultrasonication assisted synthesis). The structures of the new compounds were elucidated using spectroscopic methods. The title products were assessed for their antimicrobial, antioxidant, and antiproliferative activities using numerous assays. Promisingly, the investigated compounds mainstream revealed promising antibacterial and anticancer activities. Thereafter, the investigated compounds' expected mode of action was debated by using an array of in silico studies. Compounds A2 and A3 were the most promising antimicrobial agents, while compounds A2, A5, and A7 revealed the most cytotoxic activities. Accordingly, RMSD, RMSF, Rg, and SASA analyses of compounds A2 and A3 were performed, and MMPBSA was calculated. Lastly, the ADMET (absorption, distribution, metabolism, excretion, and toxicity) analyses of the novel acridine derivatives were investigated. The tested compounds' existing screening results afford an inspiring basis leading to developing new compelling antimicrobial and anticancer agents based on the acridine scaffold., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Background: Fabaceae plays a crucial role in African traditional medicine as a source of large number of important folk medication, agriculture and food plants. In a search of potential antioxidant and anti-inflammatory candidates derived from locally cultivated plants, the flowers of Tipuana tipu (Benth.) Lillo growing in Egypt were subjected to extensive biological and phytochemical studies. The impact of the extraction technique on the estimated biological activities was investigated., Methods: The flowers were extracted using different solvents (aqueous, methanol, water/methanol (1:1), methanol/methylene chloride (1:1), and methylene chloride). The different extracts were subjected to antioxidant (DPPH, ABTS, and FRAP) and anti-inflammatory (COX-2 and 5-LOX) assays. The methanol extract was assessed for its inhibitory activity against iNOS, NO production, and pro-inflammatory cytokines (NF-KB, TNF-R 2 , TNF-α, IL-1β, and IL-6) in LPS-activated RAW 264.7 macrophages. The composition-activity relationship of the active methanol extract was further investigated using a comprehensive LC-QTOF-MS/MS analysis. The major identified phenolic compounds were further quantified using HPLC-DAD technique. The affinity of representative compounds to iNOS, COX-2, and 5-LOX target active sites was investigated using molecular docking and molecular dynamics simulations., Results: The methanol extract exhibited the highest radical scavenging capacity and enzyme inhibitory activities against COX-2 and 5-LOX enzymes with IC 50 values of 10.6 ± 0.4 and 14.4 ± 1.0 µg/mL, respectively. It also inhibited iNOS enzyme activity, suppressed NO production, and decreased the secretion of pro-inflammatory cytokines. In total, 62 compounds were identified in the extract including flavonoids, coumarins, organic, phenolic, and fatty acids. Among them 18 phenolic compounds were quantified by HPLC-DAD. The highest docking scores were achieved by kaempferol-3-glucoside and orientin. Additionally, molecular dynamics simulations supported the docking findings., Conclusion: The flower could be considered a potentially valuable component in herbal medicines owing to its unique composition and promising bioactivities. These findings encourage increased propagation of T. tipu or even tissue culturing of its flowers for bioprospecting of novel anti-inflammatory drugs. Such applications could be adopted as future approaches that benefit the biomedical field., (© 2024. The Author(s).)

The present study describes synthesizing a novel series of polyfunctionalized pyridine congeners 1-18 and assessed for cytotoxic efficacies versus HCT-116, MCF-7, and HepG-2 among one non-cancerous BJ-1 human normal cell. Most compounds were precisely potent anticancer candidate drugs. The molecular impact of the most active compounds 9, 10, 11, 13, 15, and 17 was evaluated after MCF-7 treatment. The gene expression of pro- and ant-apoptosis markers P53, Bax, Caspase-3 and Bcl-2 as well as VEGFR-2 and HER2 were determined. Compounds 13 and 15 induced upregulation of pro-apoptosis of P53, Bax, Caspase-3 and downregulation of anti-apoptosis Bcl-2 gene. However, compound 15 showed higher effect compared to 13 and respective control. Moreover, a slight reduction in HER2 gene expression was detected due to compound 15 treatment, while VEGFR-2 gene was upregulated. In agreement, the immunoblotting analysis showed higher accumulation of P53, Bax, Caspase-3 proteins and of decrease the Bcl-2 protein levels. Furthermore, docking studies united with molecular dynamic simulation exposed compounds 13 and 15 fitting in the middle of the active site at the interface linking the ATP binding site and the allosteric hydrophobic binding pocket. Finally, we performed Petra/Osiris/ Molinspiration (POM) analysis for the newly synthesized compounds. The evaluation of primary in silico parameters revealed significant differences among individual polyfunctionalized pyridine compounds, highlighting the most promising candidates. These preliminary results may help in coordinating and initiating other research projects focused on polyfunctionalized pyridine compounds, especially those with predicted bioactivity, low toxicity, optimal ADME parameters, and promising perspectives., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Anacyclus pyrethrum L. (Akarkara root), a valuable Ayurvedic remedy, is reported to exhibit various pharmacological activities. Akarkara root was subjected to bioassay-guided fractionation, to isolate its active constituents and discover their potential bioactivities, followed by computational analysis., Methods: The methanol extract and its fractions, methylene chloride, and butanol, were assessed for their antioxidant, anti-inflammatory, and anticholinergic potentials. The antioxidant activity was determined using DPPH, ABTS, FRAP, and ORAC assays. The in vitro anticholinergic effect was evaluated via acetyl- and butyryl-cholinesterase inhibition, while anti-inflammatory effect weas determined using COX-2 and 5-LOX inhibitory assays. The methylene chloride fraction was subjected to GC/MS analysis and chromatographic fractionation to isolate its major compounds. The inhibitory effect on iNOS and various inflammatory mediators in LPS-activated RAW 264.7 macrophages was investigated. In silico computational analyses (molecular docking, ADME, BBB permeability prediction, and molecular dynamics) were performed., Results: Forty-one compounds were identified and quantified and the major compounds, namely, oleamide (A1), stigmasterol (A2), 2E,4E-deca-2,4-dienoic acid 2-phenylethyl amide (A3), and pellitorine (A4) were isolated from the methylene chloride fraction, the most active in all assays. All compounds showed significant in vitro antioxidant, anticholinergic and anti-inflammatory effects. They inhibited the secretion of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in activated RAW macrophages. The isolated compounds showed good fitting in the active sites of acetylcholinesterase and COX-2 with high docking scores. The ADME study revealed proper pharmacokinetics and drug likeness properties for the isolated compounds. The isolated compounds demonstrated high ability to cross the BBB and penetrate the CNS with values ranging from 1.596 to -1.651 in comparison with Donepezil (-1.464). Molecular dynamics simulation revealed stable conformations and binding patterns of the isolated compounds with the active sites of COX-2 and acetyl cholinesterase., Conclusions: Ultimately, our results specify Akarkara compounds as promising candidates for the treatment of inflammatory and neurodegenerative diseases., (© 2023. The Author(s).)

This study aims to isolate the active constituents of Pyrus pyrifolia Nakai fruits using a bioassay-guided fractionation approach, test their activity in vitro against key enzymes for metabolic disorders, and support it with molecular docking simulations. The antioxidant potential of the methanolic extract (ME), its polar (PF), and non-polar fractions (NPF), along with the inhibitory activity against α-glucosidase, α-amylase, lipase, angiotensin I converting enzyme (ACE), renin, inducible nitric oxide synthase (iNOS), and xanthine oxidase (XO) were assessed. The PF exhibited the highest antioxidant and enzyme inhibitory activity. Purification of PF yielded rutin, isoquercitrin, isorhamnetin-3-O-β-D-glucoside, chlorogenic acid, quercetin, and cinnamic acid. HPLC-UV analysis of the PF allowed for the quantification of 15 phenolic compounds, including the isolated compounds. Cinnamic acid was the most powerful antioxidant in all assays and potent enzyme inhibitor against the tested enzymes (α-glucosidase, α-amylase, lipase, ACE, renin, iNOS, and XO). Additionally, it showed high affinity to target α-glucosidase and ACE active sites with high docking scores (calculated total binding free energy (ΔGbind) -23.11 kcal/mol and - 20.03 kcal/mol, respectively]. A 20-ns molecular dynamics simulation using MM-GBSA analysis revealed a stable conformation and binding patterns in a stimulating environment of cinnamic acid. Interestingly, the isolated compounds' dynamic investigations including RMSD, RMSF, and Rg demonstrated a stable ligand - protein complex to the active site of iNOS with ΔGbind ranging from - 68.85 kcal/mol to -13.47 kcal/mol. These findings support the notion that P. pyrifolia fruit is a functional food with multifactorial therapeutic agents against metabolic syndrome-associated diseases., (© 2023. The Author(s).)

In this research study, the authors successfully synthesized potent new anticancer agents derived from indazol-pyrimidine. All the prepared compounds were tested for in vitro cell line inhibitory activity against three different cancerous cell lines. Results demonstrated that five of the novel compounds- 4f , 4i , 4a , 4g , and 4d -possessed significant cytotoxic inhibitory activity against the MCF-7 cell line, with IC 50 values of 1.629, 1.841, 2.958, 4.680, and 4.798 μM, respectively, compared to the reference drug with an IC 50 value of 8.029 μM, thus demonstrating promising suppression power. Compounds 4i , 4g , 4e , 4d , and 4a showed effective cytotoxic activity stronger than the standard against Caco2 cells. Moreover, compounds 4a and 4i exhibited potent antiproliferative activity against the A549 cell line that was stronger than the reference drug. The most active products, 4f and 4i , werr e further examined for their mechanism of action. It turns out that they were capable of activating caspase-3/7 and, therefore, inducing apoptosis. However, produced a higher safety profile than the reference drug, towards the normal cells (MCF10a). Furthermore, the dynamic nature, binding interaction, and protein-ligand stability were explored through a Molecular Dynamics (MD) simulation study. Various analysis parameters (RMSD, RMSF, RoG, and SASA) from the MD simulation trajectory have suggested the stability of the compounds during the 20 ns MD simulation study. In silico ADMET results revealed that the synthesized compounds had low toxicity, good solubility, and an absorption profile since they met Lipinski's rule of five and Veber's rule. The present research highlights the potential of derivatives with indazole scaffolds bearing pyrimidine as a lead compound for designing anticancer agents.

Acacia nilotica (synonym: Vachellia nilotica (L.) P.J.H.Hurter and Mabb.) is considered an important plant of the family Fabaceae that is used in traditional medicine in many countries all over the world. In this work, the antiviral potentialities of the chemically characterized essential oils (EOs) obtained from the bark and fruits of A. nilotica were assessed in vitro against HAV, HSV1, and HSV2. Additionally, the in silico evaluation of the main compounds in both EOs was carried out against the two proteins, 3C protease of HAV and thymidine kinase (TK) of HSV. The chemical profiling of the bark EOs revealed the identification of 32 compounds with an abundance of di- (54.60%) and sesquiterpenes (39.81%). Stachene (48.34%), caryophyllene oxide (19.11%), and spathulenol (4.74%) represented the main identified constituents of bark EO. However, 26 components from fruit EO were assigned, with the majority of mono- (63.32%) and sesquiterpenes (34.91%), where trans -caryophyllene (36.95%), Z -anethole (22.87%), and γ-terpinene (7.35%) represented the majors. The maximum non-toxic concentration (MNTC) of the bark and fruits EOs was found at 500 and 1000 µg/mL, respectively. Using the MTT assay, the bark EO exhibited moderate antiviral activity with effects of 47.26% and 35.98% and a selectivity index (SI) of 2.3 and 1.6 against HAV and HSV1, respectively. However, weak activity was observed via the fruits EO with respective SI values of 3.8, 5.7, and 1.6 against HAV, HSV1, and HSV2. The in silico results exhibited that caryophyllene oxide and spathulenol (the main bark EO constituents) showed the best affinities (ΔG = -5.62, -5.33, -6.90, and -6.76 kcal/mol) for 3C protease and TK, respectively. While caryophyllene (the major fruit EO component) revealed promising binding capabilities against both proteins (ΔG = -5.31, -6.58 kcal/mol, respectively). The molecular dynamics simulation results revealed that caryophyllene oxide has the most positive van der Waals energy interaction with 3C protease and TK with significant binding free energies. Although these findings supported the antiviral potentialities of the EOs, especially bark EO, the in vivo assessment should be tested in the intraoral examination for these EOs and/or their main constituents.

Garlic (known as; Allium sativum) is one of the most widely used medicinal plants in the world. Allicin is the major agent of garlic that gives its known pharmacological activities as anti-inflammatory, antibacterial, antifungal, antiviral and antioxidant agent. It could be extracted from bulbs of Allium sativum by water extraction to give allicin in low yield therefore other better methods were followed for extraction such as ultrasonic-assisted method that gives good yield. Attempts to optimize allicin extraction were found with sliced garlic at 25 °C for 90 minute of extraction for maximum yield (112μg/mL). Allicin was subjected to its evaluation as anti-herpetic against herpes simplex virus 1 (HSV-1) and exhibited a promising activity compared to acyclovir which was used as a reference standard. On the other hand, a novel synthetic amantadine derivative was evaluated as antiherpetic agent and prepared from the reaction of 2-thiouracil-5-sulphonyl chloride with amantadine hydrochloride in pyridine. The synergestic effect of allicin and the amantadine derivative was evaluated against HSV-1, using both in silico molecular docking as for dynamics simulations. Thymidine kinase target enzyme was chosen to analyze any possible interactions, as well as any protein-ligand stability. Furthermore, some of properties of the potential HSV-1 thymidine kinase target inhibitor of the amantadine derivative were analyzed.

Background: The current work planned to evaluate Cordia africana Lam. stem bark, a traditionally used herb in curing of different ailments in Africa such as gastritis and wound infections, based on phytochemical and antibacterial studies of two pathogenic microorganisms: methicillin-resistant Staphylococcus aureus (MRSA) and Helicobacter pylori ., Methods: High performance liquid chromatography (HPLC) profiling was used for qualitative and quantitative investigation of the ethanol extract. The minimum inhibitory concentration (MIC) of the ethanolic extract and isolated compounds was estimated using the broth microdilution method and evidenced by molecular dynamics simulations., Results: Four compounds were isolated and identified for the first time: α-amyrin, β -sitosterol, rosmarinic acid (RA) and methyl rosmarinate (MR). HPLC analysis illustrated that MR was the dominant phenolic acid. MR showed the best bacterial inhibitory activity against MRSA and H. pylori with MIC 7.81 ± 1.7 μg/mL and 31.25 ± 0.6, respectively, when compared to clarithromycin and vancomycin, respectively., Conclusion: The antibacterial activity of the stem bark of Cordia africana Lam. was evidenced against MRSA and H. pylori . Computational modeling of the studied enzyme-ligands systems reveals that RA and MR can potentially inhibit both MRSA peptidoglycan transpeptidases and H. pylori urease, thereby creating a pathway via the use of a double target approach in antibacterial treatment.

The constitutive BCR-ABL1 active protein fusion has been identified as the main cause of chronic myeloid leukemia. The emergence of T334I and D381N point mutations in BCR-ABL1 confer drug resistance. Recent experimental studies show a synergistic effect in suppressing this resistance when Nilotinib and Asciminib are co-administered to target both the catalytic and allosteric binding site of BCR-ABL1 oncoprotein, respectively. However, the structural mechanism by which this synergistic effect occurs has not been clearly elucidated. To obtain insight into the observed synergistic effect, molecular dynamics simulations have been employed to investigate the inhibitory mechanism as well as the structural dynamics that characterize this effect. Structural dynamic analyses indicate that the synergistic binding effect results in a more compact and stable protein conformation. In addition, binding free energy calculation suggests a dominant energy effect of nilotinib during co-administration. van der Waals energy interactions were observed to be the main energy component driving this synergistic effect. Furthermore, per-residue energy decomposition analysis identified Glu481, Ser453, Ala452, Tyr454, Phe401, Asp400, Met337, Phe336, Ile334, And Val275 as key residues that contribute largely to the synergistic effect. The findings highlighted in this study provide a molecular understanding of the dynamics and mechanisms that mediate the synergistic inhibition in BCR-ABL1 protein in chronic myeloid leukemia treatment.

A new series of Schiff bases containing benzіmidazole moiety 11-17 were synthesized by the reaction of 4-(1H-benzо[d]іmіdazоl-2-yl)anіline (1) with different aromatic aldehydes (4-10) via conventional heating and microwave irradiation methods. The structures of the novel Schiff bases were characterized by using different spectral data. Also, metal complexes 18-21 of compound 13 were synthesized, and their structure was confirmed by spectral measurements (IR, NMR, UV), molar conductivity, magnetic susceptibility and thermo-gravimetric analysis. The novel synthesized ligand 13 and its complexes 18-21 were tested for their in vitro antitumor activities towards breast, liver and lung cancer cell lines. Also, the acute toxicity of the prepared compounds 13 and 18-21 was determined in vivo. The results showed that the newly synthesized compounds 13 and 18-21 exhibited a significant activity against cancer, especially for complex 21, compared to standard drug doxorubicin. The molecular docking of complexes 20 and 21 has been also studied as Aurora kinase inhibitors.

Bcr-Abl is an oncogenic fusion protein which expression enhances tumorigenesis, and has been highly associated with chronic myeloid leukemia (CML). Acquired drug resistance in mutant Bcr-Abl has enhanced pathogenesis with the use of single therapy agents such as nilotinib. Moreover, allosteric targeting has been identified to consequentially inhibit Bcr-Abl activity, which led to the recent development of ABL-001 (asciminib) that selectively binds the myristoyl pocket. Experimental studies have revealed that the combination of nilotinib and ABL-001 induced a 'bent' conformation in the C-terminal helix of Bcr-Abl; a benchmark of inhibition, thereby exhibiting a greater potency in the treatment of CML, surmounting the setbacks of drug resistance, disease regression and relapse. Therefore, we report the first account of the dynamics and conformational analysis of oncogenic T334I Bcr-Abl by dual targeting. Our findings revealed that unlike in the Bcr-Abl-Nilotinib complex, dual targeting by both inhibitors induced the bent conformation in the C-terminal helix that varied with time. This was coupled with significant alteration in Bcr-Abl stability, flexibility, and compactness and an overall structural re-orientation inwards towards the hydrophobic core, which reduced the solvent-exposed residues indicative of protein folding. This study will facilitate allosteric targeting and the design of more potent allosteric inhibitors for resistive target proteins in cancer., (© 2018 Wiley-VHCA AG, Zurich, Switzerland.)

Recently a dramatic development of the cancer drug discovery has been shown in the field of targeted cancer therapy. Checkpoint kinase 2 (Chk2) inhibitors offer a promising approach to enhance the effectiveness of cancer chemotherapy. Accordingly, in this study many pyrimidine-benzimidazole conjugates were designed and twelve feasible derivatives were selected to be synthesized to investigate their activity against Chk2 and subjected to study their antitumor activity alone and in combination with the genotoxic anticancer drugs cisplatin and doxorubicin on breast carcinoma, (ER+) cell line (MCF-7). The results indicated that the studied compounds inhibited Chk2 activity with high potency (IC 50  = 5.56 nM - 46.20 nM). The studied candidates exhibited remarkable antitumor activity against MCF-7 (IG 50  = 6.6  μM - 24.9 μM). Compounds 10a-c, 14 and 15 significantly potentiated the activity of the studied genotoxic drugs, whereas, compounds 9b and 20-23 antagonized their activity. Moreover, the combination of compound 10b with cisplatin revealed the best apoptotic effect as well as combination of compound 10b with doxorubicin led to complete arrest of the cell cycle at S phase where more than 40% of cells are in the S phase with no cells at G2/M. Structure-activity relationship was discussed on the basis of molecular modeling study using Molecular modeling Environment program (MOE)., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Aim: Targeting aldose reductase enzyme with 2,4-thiazolidinedione-3-acetic acid derivatives having a bulky hydrophobic 3-arylquinazolinone residue., Materials & Methods: All the target compounds were structurally characterized by different spectroscopic methods and microanalysis, their aldose reductase inhibitory activities were evaluated, and binding modes were studied by molecular modeling., Results: All the synthesized compounds proved to inhibit the target enzyme potently, exhibiting IC 50 values in the nanomolar/low nanomolar range. Compound 5i (IC 50  = 2.56 nM), the most active of the whole series, turned out to be almost 70-fold more active than the only marketed aldose reductase inhibitor epalrestat., Conclusion: This work represents a promising matrix for developing new potential therapeutic candidates for prevention of diabetic complications through targeting aldose reductase enzyme. [Formula: see text].

A series of quinazolinone-based rhodanine-3-acetic acids was synthesized and tested for in vitro aldose reductase inhibitory activity. All the target compounds displayed nanomolar activity against the target enzyme. Compounds 3a, 3b, and 3e exhibited almost 3-fold higher activity as compared to the only marketed reference drug epalrestat. Structure-activity relationship studies indicated that bulky substituents at the 3-phenyl ring of the quinazolinone moiety are generally not tolerated in the active site of the enzyme. Insertion of a methoxy group on the central benzylidene ring was found to have a variable effect on ALR-2 activity depending on the nature of peripheral quinazolinone ring substituents. Removal of the acetic acid moiety led to inactive or weakly active target compounds. Docking and molecular dynamic simulations of the most active rhodanine-3-acetic acid derivatives were also carried out, to provide the basis for further structure-guided design of novel inhibitors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Influenza A virus is a negative RNA stranded virus of the family Orthomyxoviridae , and represents a major public health threat, compounding existing disease conditions. Influenza A virus replicates rapidly within its host and the segmented nature of its genome facilitates re-assortment, whereby whole genes are exchanged between influenza virus subtypes during replication. Antiviral medications are important pharmacological tools in influenza virus prophylaxis and therapy. However, the use of currently available antiviral is impeded by sometimes high levels of resistance in circulating virus strains. Here, we identified novel anti-influenza compounds through screening of chemical compounds synthesized de novo on human lung epithelial cells. Computational and experimental screening of extensive and water soluble compounds identified novel influenza virus inhibitors that can reduce influenza virus infection without detectable toxic effects on host cells. Interestingly, the indicated active compounds inhibit viral replication most likely via interaction with cell receptors and disturb influenza virus entry into host cells. Collectively, screening of new synthesis chemical compounds on influenza A virus replication provides a novel and efficacious anti-influenza compounds that can inhibit viral replication via disturbing virus entry and indicates that these compounds are attractive candidates for evaluation as potential anti-influenza drugs.

A one-pot reaction of 6-methyl-3-thioxo-3,4-dihydro-[1,2,4]triazin-5-one 1 with selected aldehydes 2a-d and chloroacetic acid afforded the respective 2-arylidene-6-methyl-thiazolo[3,2-b][1,2,4]triazine-3,7-diones 4a-d. Compunds 4a-d could be also obtained via the reaction of 1 with chloroacetic acid in refluxing acetic acid to give 6-methyl-thiazolo[3,2-b][1,2,4]triazine-3,7-dione 3 then, Knoevenagel condensation of 3 with aldehydes 2a-d gave compounds 4a-d. Heterocyclization of 4a-c with hydrazine hydrate and phenylhy- drazine gave the corresponding pyrazolines 5a-c and 6a-c, respectively. Moreover, 7-amino-9-(aryl)-3-methyl-2-oxo-2H-pyrido[2',3':4,5][1,3]thiazolo[3,2-b][1,2,4]triazine-8-carbonitrles 7a-c were synthesized by the reaction of 4a-c with malononitrile in the presence of ammonium acetate. The structures of newly synthesized compounds were confirmed by analytical and spectroscopic measurements. Some selected new compounds were screened for their cytotoxic activities against three human cancer cell lines (HepG2, MCF-7 and A549) using SRB assay and the structure-activity relationship (SAR) was discussed. The biochemical assays including antioxidant enzyme, oxidative stress and estimation of nucleic acids and proteins have been discussed for some selected compounds. The molecular docking of 4c and 7b has been also studied.

A newly synthesized series of anticancer compounds comprising thiazolo[3,2-a]pyrimidine derivatives 6a-q bearing a benzimidazole moiety was produced via a one-pot reaction of N-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-2-cyanoacetamide 5 with 2-aminothiazole and an appropriate aromatic aldehyde. Compound 7 was obtained via the reaction of 4-(1H-benzo[d]imidazol-2yl)benzenamide 1 with carbon disulphide and methyl iodide in the presence of concentrated aqueous solution of NaOH, then treated with o-phenylenediamine to give N-(4-1H-benzo[d]imidazol-2-yl)phenyl)-1H-benzo[d]imidazol-2-amine 8. The structures of the newly synthesized compounds were confirmed by analytical and spectroscopic measurements (IR, MS, and (1) H NMR). The synthesized products were screened and studied for their in vitro antitumor activity against three human cancer cell lines (namely colorectal cancer cell line HCT116, human liver cancer cell line HepG2, and human ovarian cancer cell line A2780) and their Aurora A kinase and KSP inhibitory activities. All newly synthesized compounds revealed marked results comparable with the standard drug CK0106023. The compounds 6e and 6k of the thiazolopyrimidine derivatives were the most active compounds when tested against the three cell lines in comparison with the standard drug CK0106023, and showed potent dual KSP and Aurora A kinase inhibition., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Benzimidazole ring system is found in many bioactive heterocyclic compounds because of their diverse biological and clinical applications. Furthermore, benzimidazole derivatives are structural isosters of naturally occurring nucleotides, thus they can interact with biological macromolecules such as proteins, enzymes and receptors. This review discusses the benzimidazole derivatives which possess anticancer activity of medicinal efficacy.