Introduction: Non-Small Cell Lung Cancer (NSCLC) remains a major clinical challenge and is one of the leading causes of cancer-related mortality worldwide. Its poor prognosis is driven by substantial molecular heterogeneity, dynamic interactions between tumor cells and the surrounding microenvironment, and the frequent development of therapeutic resistance. Among the signaling pathways involved, Focal Adhesion Kinase (FAK) and Proline-rich tyrosine Kinase 2 (PYK2) have emerged as important regulators that integrate oncogenic and microenvironmental signals, thereby promoting tumor progression and resistance to therapy. Methods: A narrative literature review was conducted using major scientific databases to evaluate the mechanistic, preclinical, and clinical evidence regarding the role of FAK/PYK2 signaling in NSCLC. Studies investigating pathway interactions, mechanisms of therapeutic resistance, combination treatment strategies, and nanocarrier-mediated drug delivery systems were critically analyzed. Results: FAK and PYK2 function as central signaling hubs that connect key oncogenic pathways, including Epidermal Growth Factor Receptor (EGFR), Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/AKT), Mitogen-Activated Protein Kinase (MAPK), and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling. Activation of these kinases promotes cell proliferation, survival, epithelial–mesenchymal transition, and therapeutic resistance. Although FAK/PYK2-targeted monotherapy has demonstrated limited clinical efficacy, rational combination strategies involving EGFR tyrosine kinase inhibitors, MAPK inhibitors, chemotherapy, or immunotherapy have shown promising synergistic effects. In addition, nanocarrier-based delivery systems may improve drug targeting and pharmacokinetic profiles while reducing systemic toxicity. Discussion: The adaptive quality of the disease calls for multi-pathway therapeutic strategies for the treatment of NSCLC. Blocking FAK/PYK2 may interrupt the integrated signaling pathways and compensatory mechanisms that contribute to resistance. Precision-guided combination regimens aided by the use of biomarker-driven patient selection are critical when it comes to improving clinical outcomes. Conclusion: FAK and PYK2 represent promising therapeutic targets in NSCLC. Strategies involving multi-pathway inhibition and advanced drug delivery platforms offer a rational approach to suppress tumor growth and overcome therapeutic resistance. Further investigation in translational and clinical settings is warranted to establish their therapeutic potential.
Background: Neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are driven by oxidative stress, neurotransmitter imbalance, and protein aggregation, leading to progressive neuronal loss. Both plant extracts represent promising phytopharmacological sources with multitarget neuroprotective potential, warranting further isolation, in-vivo validation, and mechanistic studies. This study aims to investigate the neuroprotective potential of Barleria terminalis and Calacanthus grandiflorus through integrated in-silico and in-vitro studies targeting key AD and PD enzymes and pathways. Methods: Methanolic extracts were characterized using LC–MS and FTIR, followed by molecular docking against AChE, MAO-B, and aggregation-related proteins. In-vitro assays including AChE/MAO-B inhibition, DPPH/ABTS antioxidant tests, cytoprotective MTT assay on SH-SY5Y cells, and Thioflavin T aggregation assays were performed. Results: The identified compounds, catechin, antirrhinoside, monotropein, and swertiamarin, showed favorable relative docking scores (−8.3 to −9.5 kcal·mol⁻¹). Extracts demonstrated potent AChE (IC50 38.2 μg/mL) and MAO-B (IC50 33.7 μg/mL) inhibition, significant antioxidant activity (IC50 42–47 μg/mL), and enhanced neuronal viability (~88%). Anti-aggregatory assays showed 58– 65% inhibition of Aβ and α-synuclein fibrils. Discussion: Both plants exhibit multitarget neuroprotective action through combined antioxidant, enzyme inhibitory, and anti-aggregatory mechanisms. Conclusion: B. terminalis and C. grandiflorus are promising phytopharmacological resources for developing safe, multitarget therapeutics against AD and PD.
Introduction: The rising incidence of antimicrobial resistance necessitates the development of novel agents capable of acting on multiple microbial targets. Imidazole-based heterocycles are well recognized for their broad-spectrum antimicrobial properties. In this context, the present study focuses on the structure-based design and evaluation of a new series of 2,4,5-triphenyl imidazole derivatives as potential multi-target antimicrobial agents. Materials and Methods: A series of 2,4,5-triphenyl imidazole analogues was synthesized via a PEG-400–mediated condensation reaction involving benzil, substituted benzaldehydes, and ammonium acetate, followed by substitution with secondary amines. The synthesized compounds were structurally characterized using Fourier-transform Infrared (FTIR) spectroscopy and proton Nuclear Magnetic Resonance (¹H-NMR) spectroscopy. Antimicrobial activity was assessed using the agar diffusion method against Staphylococcus aureus and Escherichia coli as representative bacterial strains, and Candida albicans and Aspergillus niger as fungal strains. Molecular docking studies were performed against DNA gyrase B, dihydrofolate reductase, CYP51 lanosterol 14α- demethylase, and topoisomerase IIα. In silico ADMET profiling was conducted to evaluate pharmacokinetic and toxicity parameters. Results: Among the synthesized derivatives, compound PARS-10 exhibited the highest antibacterial activity, producing a zone of inhibition of 15 mm against Staphylococcus aureus. Molecular docking studies revealed that compounds PARS-1, PARS-5, and PARS-7 showed strong binding affinities for key microbial targets, indicating their potential multitarget inhibitory activity. ADMET predictions suggested that most compounds were non-hepatotoxic, with several derivatives complying with Lipinski’s rule of five. Discussion: The observed antimicrobial activity is attributed to the presence of the 2,4,5-triphenyl imidazole core, which facilitates effective interactions with multiple microbial enzymes. The docking results support the experimental findings and highlight the capability of selected compounds to simultaneously engage bacterial and fungal targets. Favorable ADMET properties further enhance the potential of these compounds as drug-like candidates. Conclusion: This study demonstrates that 2,4,5-triphenyl imidazole derivatives represent promising scaffolds for the development of novel multi-target antimicrobial agents. The combined in vitro, in silico, and ADMET results suggest that selected compounds exhibit potent antimicrobial activity and acceptable pharmacokinetic properties, warranting further optimization and biological evaluation.
Introduction: Phosphoinositide 3-kinase gamma (PI3K-γ) and delta (PI3K-δ) are critical enzymes for cell activation, immune response, pro-inflammatory pathways, and synovial cell hyperplasia, making them promising drug targets in rheumatoid arthritis (RA). This research aimed to develop new quercetin derivatives and assess their potential as PI3K-γ and PI3K-δ inhibitors through in silico studies. Methods: Schiff base derivatives (compounds 1-7) were synthesized by condensing quercetin with amine derivatives. Their structures were confirmed and characterized using TLC, melting point, FT-IR, ¹H and ¹³C NMR, and mass spectrometry. In silico studies, including molecular docking, 100 ns MD simulations, and MM/GBSA binding free energy analysis, assessed their stability against PI3K-γ and PI3K-δ, using Duvelisib as the reference inhibitor. Result: The molecular docking studies revealed that the compounds exhibited a strong affinity towards the binding sites of PI3K-γ and PI3K-δ receptors, involving hydrogen bonding and π-π interactions, in some cases even stronger than the reference ligand. The results of the MD simulation studies showed that the protein-ligand complex formation was stable, as indicated by RMSD, RMSF, hydrogen bond, and MM-GBSA calculations. Discussion: The computational study revealed that quercetin-derived molecules exhibited promising binding interactions with PI3K-γ and PI3K-δ. Compound 7 exhibited stable binding interactions during MD simulations, making it a possible lead compound for future biological studies. Conclusion: Quercetin-derived Schiff base compounds show stable inhibitory activity against PI3K-γ and PI3K-δ, making them promising candidates for further experimental validation in rheumatoid arthritis research.
Introduction: Aldose reductase (ALR2) plays a key role in the polyol pathway by catalyzing the reduction of glucose to sorbitol. Under hyperglycemic conditions, overactivation of this pathway contributes to diabetic complications, such as neuropathy, retinopathy, and nephropathy. Selective inhibition of ALR2 is thus a promising strategy for managing these complications. This study aimed to design and optimize a new class of selective ALR2 inhibitors with potential antihyperglycemic activity, combining computational modeling, synthesis, and biological evaluation. Methods: Structural analogs were designed based on pharmacophoric features known to interact with the ALR2 active site. Molecular docking was performed using the crystal structure of ALR2 (PDB ID: 1US0) to evaluate binding affinity and interactions. Compounds with favorable docking profiles were synthesized, purified, and characterized using spectroscopic methods. Their ALR2 inhibitory activity was assessed in vitro. Selected compounds were further evaluated by molecular dynamics (MD) simulations to assess binding stability using RMSD and RMSF analyses. Results: All designed compounds showed significant binding affinity for ALR2. Compounds CPD-7, 9, 11, 12, 22, 27, 30, 31, 33, and 35 exhibited superior docking scores and selectivity. Among these, CPD-9 demonstrated the highest in vitro inhibitory activity, with an IC50 of 0.311±0.07. MD simulations confirmed the stability of the ligand–ALR2 complexes, with RMSD and RMSF values ranging from 0.5 Å to 2.5 Å. Discussion: This integrated approach identified CPD-9 as a potent and selective ALR2 inhibitor with strong binding stability, highlighting its potential for treating diabetic complications through targeted ALR2 inhibition. Conclusion: This study successfully identified and optimized a novel series of aldose reductase (ALR2) inhibitors with promising antihyperglycemic potential. Computational modeling and docking studies revealed strong binding interactions of the designed analogs with the ALR2 active site, while molecular dynamics simulations confirmed the stability of these complexes.
Background: Alzheimer's, Parkinson's, and Huntington's are neurodegenerative conditions that are progressive in nature, with neuronal degeneration and toxic protein buildup. Although the brain has been the focus of most studies, recent research has highlighted the gutbrain axis, which is considered to play a significant role in disease processes. The autophagylysosomal pathway (ALP), as a major system of cellular waste clearance, has emerged as a possible mediator of this cross-talk. In the case of ALP impairment, gut-brain communication can be disrupted, and inflammation may be promoted. Method: This review examines the role of ALP dysfunction and gut-brain interaction and how it may contribute to the progression of major neurodegenerative diseases. It also outlines therapeutic approaches currently being studied, aimed at restoring ALP functionality. Databases such as PubMed, Scopus, and Google Scholar were searched to identify relevant studies published within the past decade. Both preclinical and clinical research were considered, with a focus on mechanistic information about ALP-gut-brain interactions. Results: Preclinical evidence indicates that ALP impairment disrupts gut barrier function, the microbiota community, and systemic inflammatory pathways, which may spread to the brain and promote protein aggregation and neurodegeneration. Discussion: These processes involve genes such as GBA, LRRK2, and mTOR. Probiotics, fecal microbiota transplantation (FMT), and pharmacological inducers of autophagy have been shown to have positive effects in experimental models, but the clinical evidence is limited, inconclusive, heterogeneous, and insufficient. Conclusion: Gastrointestinal homeostasis and neurodegeneration are mechanistic relationships that impair ALP. Nevertheless, although this route presents a promising option for clinical modulation in clinical experiments, its extrapolation to the effective treatment of humans is questionable and must be tested through a stringent clinical trial.
Introduction: Alzheimer’s Disease (AD) is a progressive neurological condition that causes a gradual loss of memory and cognitive abilities, primarily caused by neuronal dysfunction and cell death. Recently, Computer-Aided Drug Design (CADD) has become a powerful tool for accelerating the discovery of novel therapeutic agents targeting complex diseases such as AD Materials and Methods: In this study, a series of indoylpropyl benzamidopiperazine derivatives was systematically optimized using both two-dimensional (2D) and three-dimensional quantitative structure-activity relationships. QSAR models were developed and validated using QSARINS and Schrödinger software suites. Molecular descriptors were tested using Multiple Linear Regression (MLR) for 2D QSAR and genetic algorithm (GA)-based methods for 3D QSAR modelling. The developed models were validated via internal and external validation techniques to ensure robustness and predictive reliability. Using QSAR, 149 new analogues targeting acetylcholinesterase (AChE) and serotonin transporter (SERT) were designed. These analogues were further tested through virtual screening, ADMET profiling, and molecular docking studies against AChE and SERT targets. Results: QSAR modeling and docking studies indicate that compound 75 is the most promising dual AChE/SERT inhibitor, with strong predicted biological activity and favorable pharmacokinetic and ADMET properties. Discussion: The built QSAR models were statistically quite accurate, as shown by correlation coefficients of R² = 0.8850 for the 2D QSAR model and R² = 0.8597 for the 3D QSAR model. Six of the designed counterparts had superior expected activity and satisfactory ADMET profiles. Six of the designed analogues exhibited better predicted activity and acceptable ADMET profiles. Molecular docking investigations confirmed these findings, identifying compound 75 as the most potent dual inhibitor due to its high binding affinity and several stabilising contacts within the active sites of AChE and SERT. Conclusion: This study effectively established reliable and predictive 2D and 3D QSAR models for indoylpropyl benzamidopiperazine derivatives, providing valuable insights into the structural features governing biological activity. The combination of QSAR-based design and molecular docking enabled the identification of promising multitarget lead candidates, particularly compound 75, which has potential for further development as a therapeutic agent for Alzheimer’s disease.
introduction: This study examines in vitro study of antioxidant activity of Cenchrus biflorus (CB) leaf, root extracts in various solvents (MeOH, Hydro-ethanol, Aqueous). materials and methods: The potential components present in Cenchrus biflorus root methanol extract (CBRME) were extracted by UV- Visible, FTIR, GC-MS along with anti-inflammatory properties. Antiradical function was estimated by DPPH, FRAP and Metal chelating assays. Anti-inflammatory properties of CBRME were assessed by carrageenan-induced paw edema model. results: Highest free radical scavenging activity were discovered in methanolic extract of leaf with minimum IC50 value (50.01 ± 0.002 µg/ml) succeeded by root methanolic extract with IC50 value (51.41 ± 0.008 µg/ml). Leaf methanol extract (227 ± 0.182) showed the maximum FRAP value followed by root methanol extract (203 ± 0.162) and leaf hydro-ethanol (155.2 ± 0.521). Leaf methanol extract of Cenchrus biflorus demonstrate higher metal chelating power (53.3 ± 0.022) as compared to the other extracts of Cenchrus biflorus. UV- visible analysis showed the presence of flavonoids, terpenoids and phenols in CBRME. FTIR showed alkyl amine, alkenes, carboxylic acids, alkenes, secondary amines, alcohols groups. GC-MS analysis of CBRME revealed 38 compounds. 10,13-Octadecadienoic acid, 9,11-Octadecadienoic acid, methyl ester, (E,E)-, 9-Octadecenoic acid (Z)-, Methyl ester were known as anti-inflammatory compounds. Significant reduction in edema of treated group were observed from 1 to 4 h in dose dependent manner (200, 300, 400 mg/kg). Blood serum parameters such as SGPT (51.8±1.48), AST (66±2.44) and ALP (149.8±2.38) were also restored to normal in treated group at high dose (400 mg/kg) as similar to standard group. discussion: In order to extract a high concentration of phytochemical compounds, antioxidants, and in vitro anti-inflammatory constituents from Cenchrus biflorus for use in pharmacognosy, methanol has been recommended as the best solvent. conclusion: Result highlighted CB as source of antioxidant and anti-inflammation properties for further studies.
Introduction:: BChE is an enzyme classified as a nonspecific cholinesterase with a widespread distribution in human plasma, the liver, and the CNS. Historically viewed as a less important enzyme than AChE; however, recent data suggest that BChE has much more importance related to neurodegeneration, detoxification of chemical compounds, and variability in pharmacogenomic responses between individuals. Research has shown that both alterations in the level of BChE enzyme activity and BChE genetic polymorphisms can lead to differences in susceptibility to diseases and responses to drugs. Methods:: A systematic literature search was conducted through PubMed, Scopus, and Web of Science covering studies published between 2000 and 2024. The articles obtained from the above search engine were studied to give an overview of the literature related to the physiological and pathological aspects of BChE. Results:: According to this review, BChE plays a compensatory role in the breakdown of ACh, especially when AChE is not functioning properly. Low or high BChE levels have been linked to several diseases. In addition to the disease-related impacts of abnormal BChE levels, genetic variations such as the K-variant, unusual alleles, and fluoride-resistant forms of BChE affect its enzymatic activity and the metabolism of drugs. Discussion:: Emerging evidence suggests that BChE serves many functions in catalyzing different biocatalytic processes and has developed increased potential for use in medicine/biomedicine. Conclusion:: Research efforts on BChE should include identifying the physiological roles of BChE, developing specific and selective molecules to regulate BChE isoforms or activities, and incorporating genetic information when developing individualized treatment plans.
Aminothiazole is an important moiety exhibiting various biological properties, including antioxidant, bacteriostatic, antibiotic, anticonvulsant, anti-HIV, cytotoxic, antifungal, anti-inflammatory and neuroprotective activities. Here, we aimed to synthesise aminothiazole derivatives bearing an oxadiazole moiety and determine their inhibitory activity against the Acetylcholinesterase (AChE) enzyme. The antioxidant activity of all molecules was evaluated using the DPPH radical scavenging method. Among all derivatives, compound 3b emerged as a potential candidate, exhibiting AChE inhibitory and antioxidant activity with IC₅₀ values of 3.55 μM and 2.17 μM, respectively. In the molecular docking analysis, the best docking score was observed for the most active compound, 3b, which also showed strong in-vitro inhibition. The synthesised compound (3b) can be considered a potential lead for the further development of new compounds against Alzheimer’s disease.
Introduction: Penicillin G amidase is an industrially significant enzyme widely employed in the production of semi-synthetic β-lactam antibiotics through the hydrolysis of Penicillin G to 6- aminopenicillanic acid. Owing to its commercial importance, extensive research has focused on improving the operational stability, reusability, and catalytic efficiency of PGA through various immobilization strategies. Methods: Optimization of multiple parameters for free and immobilized Penicillin G Acylase (PGA) is critical for improving the enzyme's catalytic effectiveness, stability, and reusability in industrial and medicinal applications. This procedure entails methodically altering and analyzing variables such as substrate concentration, mechanical stability, cycle number, and storage conditions, and their effects on operational stability, pH, and temperature. PGA was optimized by entrapment on collagen hydrogel beads, resulting in collagen hydrogel + gelatin hybrid gel beads. Result: Immobilized PGA in Collagen Hydrogel + gelatin hybrid beads showed superior thermal stability, reusability, and storage stability as compared to gelatin-immobilized PGA. The entrapment of PGA onto Collagen Hydrogel + gelatin hybrid beads revealed several advantages and could be used in the production of 6-aminopenicillanic acid (6APA). Discussion: The study investigated the biochemical behavior of Penicillin G amidase (PGA) immobilized on collagen hydrogel and a collagen–gelatin bio-composite. Relative analysis focused on enzyme activity, stability, and mechanical strength, revealing insights into their appropriateness as immobilization matrices for enhanced PGA performance in industrial biocatalysis applications. Conclusion: Hydrogel + gelatin hybrid beads are more beneficial in industrial applications due to their greater stability and usability. PGA entrapment onto Hydrogel + gelatin hybrid beads has shown numerous advantages and may be useful in the manufacture of 6APA (6-aminopenicillanic acid).
Introduction: Benzodiazepines are used for their anxiolytic, antiepileptic, muscle relaxant and hypnotic effects. In vitro, diazepam is predominantly metabolized to temazepam and nordiazepam (N-desmethyldiazepam). Since acetylcholinesterase is involved in the metabolism of diazepam, inhibition of the enzyme activity may have a significant effect on the therapeutic effect of the drug. To determine the inhibitory effect of 2,2,4-trimethyl-2,3-dihydro-1H-benzo[b][1,4]diazepine on acetylcholinesterase enzyme activity by conducting a comprehensive analysis that includes: measuring the enzyme activity in the presence of various concentrations of the inhibitor, determining the type of inhibition through kinetic studies, and assessing the potential therapeutic applications of the inhibitor in conditions associated with acetylcholinesterase dysfunction. Methods: In this study, the inhibitory properties of 2,2,4-trimethyl-2,3-dihydro-1-Hbenzo[ b][1,4]diazepine on the activity of the enzyme acetylcholinesterase were tested spectrophotometrically at three different temperatures of 25℃, 30℃, and 37℃. The substance was synthesized by a condensation reaction between o-phenyldiamine and acetone in the presence of phosphorus oxychloride on solid support (MgO). The solid product was obtained by crystallization from n-hexane. Each tested sample contained an appropriate concentration of the substrate acetylcholine iodide (AChI) in the range from 1.00 to 4.00 mmol·L-1; 5,5-dithiobis(2-nitrobenzoic acid) (DTNB) concentration 3 mmolL-1, phosphate buffer (KH2PO4/K2HPO4) pH value 8, tested substance concentration (17.70, 35.40, 53.10 mmol·L-1), and acetylcholinesterase solution (AChE) activity 0.54 UmL-1. Results: Using the spectrophotometric method, it was concluded that the examined diazepine shows a competitive type of inhibition on the enzyme acetylcholinesterase. 30°C was determined to be the optimal assay temperature. The highest inhibition was observed at 25°C using 53.10 mmol·L⁻¹ of the inhibitor. As the temperature increases, the inhibition decreases. Discussion: Based on the Lineweaver-Burk diagram, we gain insight into the type of inhibition exhibited by the synthesized compound. The intercept on the ordinate remains unchanged; the slope of the line increases, and the intercept on the abscissa decreases, indicating that it is a competitive inhibition. Conclusion: Considering the results obtained by spectrophotometric analysis, it was concluded that the enzyme acetylcholinesterase follows the Michaelis-Menten model. It has been proven that the synthesized compound exhibits inhibitory properties on the activity of acetylcholinesterase.
Introduction: Antimicrobial resistance (AMR) is a growing global health challenge that poses a significant threat to public health, healthcare systems, and socioeconomic stability. The misuse and overuse of antibiotics, along with environmental factors, have accelerated the development of resistance in key antibiotic classes, including penicillins, Aminoglycosides, Macrolides, and Tetracyclines. Despite advancements in antibiotic discovery, the rise of resistant microorganisms continues to jeopardize the efficacy of life-saving treatments. This study aims to provide a comprehensive analysis of AMR, focusing on its sources, mechanisms, and impacts. Specific objectives include exploring the historical supremacy of antibiotics, reviewing 10 FDA-approved antibiotics from 2020–2024 with 23 combination therapy drugs, investigating chemical strategies against AMR, and proposing solutions to combat resistance, particularly in widely used antibiotic classes. The paper also aims to highlight the environmental influence on AMR and suggest sustainable approaches to mitigate its spread. Methods: The study involved a detailed review of scientific literature, regulatory reports, and case studies related to AMR. Key areas analyzed include mechanisms of resistance development, chemical modifications of antibiotics, combination therapies, and environmental factors influencing AMR. Data on recently approved antibiotics (2020–2024) by the FDA were examined to assess progress in antibiotic development. Additionally, targeted strategies to overcome resistance in Penicillins, Aminoglycosides, Macrolides, and Tetracyclines were critically reviewed. Results: Recent FDA-approved antibiotics (2020–2024) and key drug combinations have shown progress against resistant pathogens, particularly in major antibiotic classes. However, persistent misuse, environmental factors, and limited innovation continue to drive antimicrobial resistance globally. The most important and widely used chemical combinations of drugs, including Penicillin, Tetracycline, Macrolides, and Aminoglycosides, have been highlighted in this review. Discussion: Antimicrobial resistance (AMR) is a global threat to public health, healthcare systems, and socioeconomic stability, particularly in India. Advanced therapies, chemical modifications, and CRISPR-Cas9-based approaches are being explored to counteract resistance. The environmental aspect of AMR, including wastewater, soil, and pharmaceutical pollution, is also crucial. Comprehensive monitoring and stewardship programs, interdisciplinary collaboration, and evidence-based guidelines are essential for reducing the global AMR burden. Conclusion: A multifaceted strategy combining chemical innovation, responsible use, and environmental control is essential to combat AMR. Urgent global collaboration is needed to preserve antibiotic effectiveness for future generations.
Introduction: Imidazo[1,2-a]pyridine derivatives exhibit notable antitumor and other pharmacological activities. In this work, the imidazo[1,2-a]pyridine scaffold was functionalized with a triazinone pharmacophore, similar to that found in Temozolomide, which is responsible for its antitumor activity. Methods: A series of pyrido[1’,2’:1,2]imidazo[5,4-d][1,2,3]triazinone derivatives were synthesized. Their properties were predicted in silico using online platforms, such as Molinspiration, PASS Online, and OSIRIS Property Explorer, to identify the most promising candidates. The selected compounds were subsequently evaluated for anticancer activity against the C6 glioma cell line across six concentrations (0–1000 μM) to generate dose–response profiles. Temozolomide was used as the reference drug. Results: Compared to Temozolomide, compound 7a exhibited the highest activity with a CC50 (Citotoxic Concentration 50) of 284 μM, whereas compound 7f (with an isopropyl R group) showed a CC50 of 310 μM, similar to Temozolomide 304 μM. Discussion: Three key factors influencing the antiglioma activity of imidazo[1,2-a]pyridine derivatives emerged from this study: electronic stabilization, charge density, and steric effects of the amide nitrogen, which govern the CC50. Conclusion: The study identified compound 7a as a potent candidate with comparable activity to Temozolomide. These findings support further development and optimization of pyrido[5,4- d]imidazo-1,2,3-triazinone derivatives as potential anticancer agents.
Introduction: Enhydra fluctuans, commonly referred to as water lettuce, is a widely recognized aquatic plant with significant traditional medicinal applications. Its bioactive components have been associated with various pharmacological effects, including antioxidant and anthelmintic properties. This study aimed to assess the potential antioxidant and anthelmintic activities of the aqueous extract of the aerial parts of Enhydra fluctuans. Methods: Preliminary phytochemical screening was conducted to determine the presence of bioactive constituents such as alkaloids, flavonoids, glycosides, phenolic compounds, carbohydrates, saponins, and tannins. Antioxidant activity was evaluated using the DPPH (2,2-diphenyl-1- picrylhydrazyl) radical scavenging assay, where the IC50 values of the aqueous extract and standard ascorbic acid were compared. The anthelmintic activity was assessed using the earthworm (Eisenia fetida) at three different extract concentrations (25, 50, and 100 mg/ml). Albendazole (10 mg/ml) served as the standard reference, while normal saline acted as the control. Parameters such as time to paralysis and time to death were recorded. Additionally, biochemical and histopathological analyses of the gut were performed to validate the findings. Results: Phytochemical analysis confirmed the presence of multiple bioactive compounds, supporting the plant's medicinal potential. The aqueous extract exhibited significant antioxidant activity with an IC50 value of 23.29 μg/ml, closely comparable to that of ascorbic acid (27.73 μg/ml). The anthelmintic activity demonstrated a dose-dependent effect, with the 100 mg/ml extract showing a paralysis time of 18 ±1.52 minutes and a death time of 76 ±1.28 minutes. Comparatively, albendazole- treated worms exhibited a paralysis time of 18.32 ±2.64 minutes and a death time of 54.24 ±2.18 minutes. Biochemical and gut histopathological examinations further corroborated the extract's efficacy in anthelmintic activity. Discussion: These findings highlight the potent antioxidant and anthelmintic properties of the plant's aqueous extract, demonstrating its efficacy comparable to standard drugs. The results support the plant’s therapeutic potential and warrant further investigation into its active constituents and mechanisms of action. Conclusion: The study confirms the antioxidant and anthelmintic potential of the aqueous extract of Enhydra fluctuans. The significant free radical scavenging activity and dose-dependent anthelmintic effects support its traditional medicinal use. These findings provide a scientific basis for further exploration of Enhydra fluctuans as a natural therapeutic agent, particularly in developing plant-based anthelmintic treatments.
Type 2 diabetes mellitus is a growing global public health issue, with its prevalence projected to increase in the coming decades. It is one of the most prevalent and growing global health concerns, affecting millions of individuals worldwide. The condition is classified into two primary types: Type 1 diabetes, an autoimmune disorder that leads to the destruction of insulin-producing beta cells in the pancreas, and Type 2 diabetes, which is predominantly associated with insulin resistance and inadequate insulin secretion. The various enzymes play a crucial role in the regulation of metabolic pathways, and their dysfunction can contribute to various diseases, including diabetes mellitus. Among these enzymes, the dipeptidyl peptidase-4 serves as a therapeutic target for managing T2D. Inhibiting DPP-4 prevents the breakdown of glucose-dependent insulinotropic peptide and glucagon-like peptide 1, thereby maintaining their natural levels and helping to reduce blood glucose. This review provides a comprehensive overview of the DPP-4 enzyme, including the effects of DPP-4 inhibition on pancreatic beta cell function, skeletal muscle function, and glucose-lowering mechanisms. We believe that this information will aid scientists in developing novel antidiabetic compounds for T2D treatment.
Introduction: The SARS-CoV-2 main protease (Mpro) is a critical enzyme for viral replication, making it an essential target for COVID-19 therapeutic development. In this study, we conducted a comprehensive virtual screening campaign to identify natural product-derived Mpro inhibitors using both structure-based pharmacophore modeling and ligand-based similarity search. Methods: Two optimized pharmacophore models were constructed from Mpro crystallographic structures (PDB codes 7QBB and 7TIA), validated through ROC analysis, optimized using Dynophores dynamic simulations, and used to screen two natural product libraries. The ligand-based screening was also performed using the co-crystallized ligands of these models, capturing compounds with high shape and atom-based similarity. Results: Two rounds of molecular docking were performed to filter and refine the hits, leading to the identification of 17 promising compounds with favorable binding interactions and physicochemical profiles. Molecular dynamics simulations of top hits demonstrated stable binding within the Mpro active site, with binding energies supporting their potential as potent inhibitors. Discussion:: The integration of dynamic pharmacophore modeling (dynophore) represents a significant advancement over static models by accounting for protein-ligand interaction flexibility during molecular dynamics. This dynamic approach not only improves hit specificity but also reduces false positives, thereby enhancing the reliability of the virtual screening process. Furthermore, the identification of compound 10313 with high binding stability underscores the predictive value of combining pharmacophore filtering with MD simulations. Conclusion: This study highlights the value of natural products as a reservoir for Mpro inhibitors, presenting novel candidates for further experimental validation in the fight against COVID-19.
Introduction: Caftaric acid (CFA), a natural product, has been experimentally proven to have diverse pharmacological properties. The nexus of NF-kB/VEGF/MMP9 signaling is believed to be associated with angiogenesis and vascular complications in patients with diabetic retinopathy (DR). The aim and objectives of the study are to explore the therapeutic relevance of CFA in DR, particularly focusing on pathological angiogenesis mechanisms involving the NF-κB / VEGF / MMP-9 signaling pathway associated with DR. To assess the anti-angiogenic potential of CFA using the CAM (Chorioallantoic Membrane) and cell culture-based models. Methods: The cytotoxicity screening of CFA was performed using Human Retinal Pericyte cells (HRPCs). In vitro free radical (DPPH, OH, NO) assays were performed for CFA and standard ascorbic acid. An in vitro CAM assay of CFA and standard bevacizumab (15 μg/mL) was performed to assess angiogenesis in the CAM. In vivo STZ assay for CFA (100 and 200 mg/kg; oral) and standard epalrestat (150mg/kg/day; oral) were performed to observe the intensity of DR by using male Wistar albino rats. After the last dose of test and standard drug administration, all animals were sacrificed to carry out biochemical, western blotting, and histopathological analysis. Results: The CFA showed concentration-dependent scavenging activity of DPPH, NO, and OH radicals comparable to that of the standard ascorbic acid. Significant antiangiogenic effects were observed for CFA (100 and 250 μg/mL), with scores of 1 and 1.6, respectively. CFA (200μg/mL; CAM model) and CFA (200 mg/kg; STZ model) significantly reduce VEGF, MMP9, and NF-κB expressions. Discussion: VEGF and MMP9 are major drivers of angiogenesis and vascular permeability, and their inhibition by CFA suggests a reduction in retinal angiogenesis and vascular leakage. Its mechanism involves modulation of the NFκB/VEGF/MMP-9 signaling pathway, leading to reduced pathological angiogenesis in both in vitro and in vivo models. This reinforces the CFA's potential in mitigating the pathological features of DR. Conclusion: CFA demonstrates significant anti-angiogenic and anti-inflammatory potential by suppressing MMP-9 activity and expression. These findings suggest that CFA could serve as a promising therapeutic candidate for managing diabetic retinopathy by targeting abnormal angiogenesis and inflammation.
Introduction: Phytase enzyme catalyzes the hydrolysis of phytate, an anti-nutrient compound present in cereals and grains, to release orthophosphate and myo-inositol hexakisphosphate with lower degrees of phosphorylation, with metal ions, proteins, and starch chelated to phytate naturally. The study aimed to screen potential phytase-producing bacterial isolates and characterize the extracellular phytase of the bacterial isolate with the best phytase activity. Methods: A promising isolate (R5-C2-C4) out of thirty tested bacterial strains, which showed the best hydrolysis efficiency on Phytase Selective Medium (PSM) plates, was selected to investigate phytase production in Liquid Phytase Selective Medium (LPSM) under constant conditions of 37°C and pH 7.0 during a 72-hour incubation period, with measurements taken at 24-hour intervals using phytase production activity assay. Results: The local isolate Bacillus subtilis (C4) was found to produce significantly the highest phytase activity of 0.818 Unit/ml out of the tested isolates during 72 h of incubation at 37°C with the pH of 7.0 as a characterization of crude phytase. Discussion: Enzyme activity and stability under varying pH and temperature conditions are always a significant challenge during food and feed processing. Most studies indicate that bacterial phytase and especially Bacillus sp. phytase had a pH optimum of (6.5-7.5), and optimum temperature of (35-60)°C, where the phytase parameters of this study isolate, Bacillus subtilis found to be in the same range. Conclusion: The local isolated Bacillus subtilis produces its significant amount of phytase with ideal production parameters, which would considerably make it useful for applications in feed and food.
Introduction: Tuberculosis is a life-threatening infectious disease and a major public health concern. The recent emergence of extensively and totally resistant strains of Mycobacterium tuberculosis has driven the search for new antituberculosis agents with previously unexploited mechanisms of action. The main aim of this study is to develop inhibitors with dual-targeted activity toward M. tuberculosis leucyl-tRNA synthetase (LeuRS) and methionyl-tRNA synthetase (MetRS). Methods: In order to find M. tuberculosis LeuRS and MetRS inhibitors, virtual screening was performed with AutoDock software. The top-scoring compounds were then evaluated in vitro in aminoacylation assay using radioactive [14C]-L-leucine. Results: The low molecular weight inhibitors targeting M. tuberculosis LeuRS were identified among Benzo[b]oxepine-4-carboxylic acid (5-benzyl-thiazol-2-yl)-amide derivatives. Discussion: The most active compound – 7-Methoxy-benzo[b]oxepine-4-carboxylic acid [5-(2- fluoro-benzyl)-thiazol-2-yl]-amide, inhibited mycobacterial LeuRS with IC50 value of 19.7 μM. It was found that this compound inhibits M. tuberculosis MetRS by 96.5% at the concentration of 100 μM. Based on molecular docking results, the compounds from this class bind simultaneously to adenine recognition region and amino acid acceptor region of M. tuberculosis aminoacyl-tRNA synthetases synthetic sites. Conclusion: Benzo[b]oxepine-4-carboxylic acid (5-benzyl-thiazol-2-yl)-amide derivatives can be the basis for chemical optimization and biological investigations.
