Urease enzyme is crucial to the nitrogen metabolism of plants during seed germination, and it plays a major role in the pathophysiology of gastric and peptic ulcers, since it enables Helicobacter pylori to survive in the low pH of the stomach. Urease-associated pathophysiology in plants and humans highlights the need for effective therapeutic and management strategies to mitigate its impact. Over the past decades, hybrid molecular conjugates of different 1H-1,2,3-triazole pharmacophores have been extensively explored in medicinal chemistry. With this aim, we designed two click-enabled libraries of novel quinoline-piperazine-linked 1H-1,2,3-triazole macromolecular scaffolds (10a-10f) using Cu(I)-catalyzed azide-alkyne cycloaddition. Their structures were elucidated using multiple advanced spectroscopic techniques (1H and 13C NMR and ESI-HRMS). X-ray crystallography unambiguously confirmed the exact structure of compound 6. All the synthetic hybrids were tested for their inhibitory potential against urease. Among all compounds, 7 and 10e exhibited excellent urease inhibition with IC50 values of 19.65 ± 3.21 µM and 21.19 ± 2.90 µM, respectively. Furthermore, molecular docking reflects stable binding of most active inhibitors (7 and 10e) within the catalytic site of urease. Overall, the combined in-vitro and in-silico outcomes reflect quinoline-piperazine-linked 1H-1,2,3-triazole macromolecular scaffolds (10a-10f), particularly analogues 7 and 10e, as promising lead molecules for further development for urease-linked diseases.

Photocatalytic oxidation using titanium dioxide (TiO2) is a well-established and sustainable technology for addressing various water treatment challenges, particularly the persistent issue of textile wastewater. This study explores the synthesis and optimization of manganese-incorporated magnetic Fe3O4/TiO2 (FeMnT) photocatalysts with enhanced photodegradation performance under visible light irradiation. The FeMnT photocatalysts were synthesized using a two-step process involving sol-gel assisted wet impregnation followed by calcination at temperatures ranging from 300 °C to 500 °C, exhibiting improved absorption in visible light, effective charge separation, and excellent photocatalytic breakdown of RY145 dye, along with easy magnetic recovery. The optimized photocatalyst, 0.75 FeMnT-300, demonstrated the highest degrading efficiency of all the produced nanocomposites, achieving 89.5% in just 60 minutes. Its enhanced structural properties, ideal photocatalyst dosage (1 g L-1), and superior adsorption-desorption equilibrium at pH 6 contribute to its high efficiency. Because of the improved light penetration and more active catalytic sites, the dye removal efficiency was also noticeably greater at lower dye concentrations (e.g., 10 mg L-1). At the calcination temperatures for both 0.75 FeMnT-3 and 0.75FeMnT-5, 100% log reduction for S. aureus and E. coli was observed under visible light with an optimal dosage of 1 mg mL-1 as the minimum bactericidal concentration (MBC), signifying efficient bacterial control. Fe3O4's magnetic properties enabled rapid nanoparticle recovery, ensuring reusability and cost-effectiveness. The molecular docking studies revealed that the photocatalyst binds strongly to the active site of β-lactamase through multiple hydrogen, ionic, and metallic interactions with key catalytic residues, displaying a highly promising binding energy (-12.70 kcal mol-1) that supports its strong bactericidal activity. Photoluminescence analysis indicated effective charge separation due to reduced emission intensity, while VSM measurements confirmed soft ferromagnetic behavior and adequate magnetization for recovery. These factors enhanced the photocatalytic performance of the optimized 0.75 FeMnT-3 photocatalysts. The strong relationship between dye discoloration and mineralization shows effective photocatalytic degradation, implying complete oxidative breakdown to give ˙OH as the main ROS species rather than partial fragmentation of the dye molecule. These findings highlight the potential of FeMnT nanocomposites for efficient and sustainable wastewater treatment applications.

The photocatalytic synthesis of hydrogen peroxide (H2O2) using water and molecular O2 under solar irradiation presents a sustainable alternative to the energy-intensive anthraquinone process. Covalent organic frameworks (COFs), with their crystalline order, tunable porosity, and molecular-level designability, have recently emerged as promising photocatalysts for this transformation. However, their performance remains limited by competing reaction pathways, sluggish charge separation, and suboptimal interaction with reactants. This Review highlights recent breakthroughs in COF-based systems for sacrificial-agent-free H2O2 generation, focusing on strategies that modulate framework composition, electronic structure, and active-site accessibility. Key approaches include the incorporation of donor–acceptor motifs, construction of heterojunctions, fine-tuning of linkage chemistry, and integration of metal or non-metal catalytic centers. The dual-pathway mechanism involving both oxygen reduction and water oxidation is critically examined, alongside insights from mechanistic and spectroscopic studies. Challenges in efficiency, selectivity, and operational stability are discussed, and future directions are proposed for the rational design of next-generation COF photocatalysts. These advances pave the way for decentralized, light-driven H2O2 generation under ambient conditions.

AIMS:The current study aimed to synthesize and evaluate benzimidazole Schiff bases as dual acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). METHODS:Ten benzimidazole Schiff bases were synthesized and characterized by spectroscopic techniques. These compounds were assessed for in vitro AChE and BuChE inhibitory activities. Density functional theory (DFT) analysis was carried out to know the electronic properties, while molecular docking studies were performed to expose protein ligand interactions. RESULTS:In the series, compounds (2c, 2f, 2h, 2a, and 2b) displayed potent inhibition against AChE and BuChE comparable to the standard galantamine. DFT study showed that compounds having higher electrophilicity (ω), lower hardness (η), higher softness (σ), and lower energy gap (ε) increase the inhibitory activity. In addition, electron donating groups at meta position of the benzene improved the potency, while docking studies confirmed favorable binding interactions with the active site of the enzymes. DISCUSSION:These consequences show that both geometric and electronic properties have a vital role in determining the cholinesterase inhibition. These derivatives facilitate multiple interactions within the enzyme active site, supporting its potential as biologically relevant nucleus. CONCLUSION:The experimental and computational findings provide valuable insights for the optimization and rational design of new therapeutic agents for Alzheimer's disease.

BACKGROUND:Medicinal plants are major sources of bioactive polyphenols. The plants of Rheum genus contain valuable phenolic compounds which exhibit various important pharmacological activities. OBJECTIVES:The current study was designed to investigate the polyphenols in Rheum wittrockii roots through bioassays and extraction/ isolate them via chromatophilic methods. METHODS:The roots biomass of R. wittrockii was extracted with methanol and fractionated into four sub-fractions, i.e. n-hexane, chloroform, ethyl acetate and n-butanol (FG1-FG4). Total Phenolic Content (TPC) assay was used to affirm the number of total phenolic contents equivalent to gallic acid. Antioxidant activities were measured via 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay. α-amylase enzyme inhibition activities were performed using standard methods. Antibacterial activities were performed against Methicillin-Resistant Staphylococcus Aureus (MRSA) in dose dependent manner for all the fractions. The FG2 fraction was subjected to series of chromatographic separation using silica gel column to isolate the main phenolic compounds. RESULTS:Chloroform fraction (FG2) showed TPC of 12.5 mg/g GAE, strong antioxidant activities i.e. 85±0.22% at dose of 100 mg/mL (IC50= 6.25 mg/mL) against DPPH and also showed strong α-amylase inhibition activities with IC50 values of 432 µg/mL, compared to IC50 of standard acarbose (125 µg/mL). It was active antibacterial against MRSA at lower doses. The FG2 fraction was further subjected to various chromatographic separations to obtain three known phenolic compounds, protocatecutic acid (1), isovanilliic acid (2) and epipinoresinol (3) in appreciable quantities for the first time from this plant. The structures of all the three compounds were elucidated through FT-IR, NMR and Mass spectral studies. CONCLUSION:The present investigation concluded that the roots of Rheum wittrockii is a good source of phenolics. Its chloroform fraction showed potent antioxidant, anti-diabetic and antibacterial effects probably due to its three compounds isolated for the first time. The compounds are valuable pharmaceuticals with promising biological actions.

Hydrogels have a vast range of applications, and they can be prepared from different composites. By combining terpolymers with biopolymers and graphene oxide, advanced materials can be formed with great strength, different functionality and flexibility; these materials can be used for different purposes. In the present work, computational modeling of hydrogels was performed where biopolymers (chitosan: CHT) was combined with terpolymers such as acrylamide (AA), acrylonitrile (AN), methacrylic acid (MAA), linker Butyl methacrylate (BMA), and graphene oxide (GO) to from four distinct nano-composites (CHT-G-Poly (AA-Co-AN-Co-MAA)/GO: HM (7 polymer, 15 BMA and zero GO), HM1 (7 polymer, 15 BMA and 3 GO), HM2 (7 polymer, 15 BMA and 6 GO) and HM3 (7 polymer, 15 BMA and 9 GO). Molecular dynamics (MD) simulation was applied to study the mechanical properties, interaction patterns, and transport properties. Mechanical properties reflect that GO gives strength and enhances the swelling properties of hydrogel composites. Molecular level interactions of polymer composites among themselves, with water and also with the (ciprofloxacin) drug were analyzed to know the hydrogel's properties and their efficacy as a drug carrier. Transport property shows that GO increases the retention time of the drug. In this study, HM3 showed highest hydrogel and drug delivery properties among HM, HM1, HM2 and HM3.

ABSTRACT In the current work, a new series of novel Δ 2 ‐pyrazoline‐1 H ‐1,2,3‐triazole derivatives ( 6a‐6j and 7a‐7f ) were synthesized, followed by in situ biological evaluation to assess their antiproliferative and immunomodulatory potential against breast cancer cells (MDA‐MB‐231 and MCF‐7), HUVECs, and PBMCs. The compounds demonstrated antiproliferative effects with IC 50 values ranging from 116.92 to 549.73 µM. Seven compounds ( 6c , 6f , 6h , 6i , 7b , 7e , and 7f ) exhibited promising antiproliferative activities with IC 50 values below 140 µM in both MDA‐MB‐231 and MCF‐7 cancer cell lines. Compound 7f demonstrated the highest antiproliferative effect with IC 50 values of 116.92 µM in MDA‐MB‐231 and 124.72 µM in MCF‐7, with an acceptable cytotoxicity profile in normal HUVEC cells (IC 50 = 208.41 µM); thus, immunomodulatory effects of 7f on checkpoint signaling were further evaluated. Compound 7f showed a dose‐dependent increase of TIGIT, PD‐1, and LAG‐3 expression in CD3 + T cells. These changes may enhance responsiveness to checkpoint‐targeted therapies while reflecting complex regulation of T‐cell function. In silico target fishing and molecular docking reflect calpain as a probable target for 7f , while DFT analysis indicates electrophilic and nucleophilic positions within 7f may help its interaction with the target. Molecular dynamics (MD) simulation supports strong binding of 7f with binding energy (−22.259 ± 4.71 kcal mol −1 ).

Background Enterococcus faecium is a major global health hazard, primarily associated with hospital-acquired infections in immunocompromised patients. E. faecium is well known for its high levels of antibiotic resistance, particularly to vancomycin. Methods In the present study, computational and advanced biophysical strategies were used for the identification of inhibitors against the vancomycin-resistant D-Alanyl-D-lactate ligase. Results Based on the lowest binding energy scores, the top three selected compounds were identified as computationally prioritized drug candidates, with binding affinity scores of -10.4, -10.2, and -10.0 kcal/mol for Top-1, Top-2, and Top-3, respectively. In comparison, the control ligand, D-alanyl-D-lactate, showed a binding affinity of -7.5 kcal/mol. These computational results specify the relative affinity of each compound for the active site, with lower (more negative) values reflecting stronger molecular interactions. The top-ranked docked complexes were then subjected to 200 ns molecular dynamics simulations to evaluate the behavior of the protein-ligand complexes under a dynamic environment. Analysis of the simulation trajectories suggested that the selected top-ranked ligands sustained favorable interactions within the binding pocket throughout the simulation period, supporting their potential as computational hits for further experimental assessment. Further, the ADMET properties analysis of the selected compounds was evaluated; according to Lipinski's rule of five, the selected compounds fall into the drug-likeness group. In the PCA analysis, the selected compounds stabilized the protein structure to varying degrees by reducing its intrinsic conformational flexibility compared to the control system. Salt bridge analysis showed that the selected compounds maintain structural integrity under physiological conditions. DFT calculations provided supportive insight into ligand electronic properties, including frontier orbital distribution, reactivity descriptors, and charge distribution, which may help rationalize interaction propensity. Conclusion Overall, the findings provide a theoretical framework for experimental biologists to formulate effective drug molecules for E. faecium.

In addition to their use as building blocks in organic synthesis, anilides are widely applied in a variety of industries, such as pharmaceutical, materials science, and agrochemical. The previously reported methods generally require transition-metal catalysts, co-catalysts, bases, solvents, and additives. Herein, we report a neat, catalyst-, and additive-free sustainable method for generating aryl radicals from arenediazonium salts and their subsequent reactions with nitriles to afford anilides under mild conditions (80 °C). The reaction features promising green chemistry metrics, including a low E-factor, a low PMI, and high mass productivity. The developed method is operationally simple and can be used for the synthesis of desired anilides in low-to-moderate and excellent yields (32-90%) with a broad substrate scope. In addition, the reaction exhibits excellent chemoselectivity, proceeding with the evolution of a nitrogen molecule to yield C-N coupling products exclusively. Furthermore, in the case of cinnamyl nitriles, the reaction was found to be 100% stereoselective, delivering only E-configured cinnamides. Mechanistic studies revealed the generation of an aryl radical via a self-sustained autoredox-active mechanism. This method of producing aryl radicals from arenediazonium ions under neat and/or catalyst-free conditions has been previously unexplored.

Novel, eco-friendly, and biocompatible bi-biopolymer magnetic composite beads were synthesized by integrating sodium alginate and agar with iron oxide (Fe3O4) and green tea-mediated manganese oxide (MnO) nanoparticles. The bi-biopolymer magnetic composite beads prepared with varying contents (10.15-30%) of MnO nanoparticles were systematically characterized using FTIR Spectroscopy, SEM, EDX, XRD, TGA, BET analysis, and electrical conductivity analyses, confirming uniform nanoparticle dispersion and strong polymer matrix-nanoparticle interactions. Among the synthesized formulations, 30%@SAMN (sodium alginate-agar magnetic nanocomposite beads) exhibited superior adsorption performance, achieving approximately 99% methylene blue removal at pH 9 using a 0.01 g adsorbent dose with equilibrium reached within 10 min. The enhanced adsorption efficiency was attributed to increased surface roughness, higher porosity, and abundant active adsorption sites resulting from higher MnO nanoparticle incorporation and synergistic interaction with Fe3O4 nanoparticles. Adsorption kinetics followed the pseudo-second-order model, while equilibrium data showed excellent agreement with the Langmuir isotherm with a maximum adsorption capacity of 61.25 mg g-1. Thermal and swelling analyses revealed enhanced crosslinking and thermal resistance with increasing MnO incorporation. The nanocomposite beads also demonstrated remarkable multifunctionality, showing strong antibacterial, antioxidant, anti-inflammatory, and antidiabetic properties along with promising hemostatic and electrical performance. Overall, the results highlight the successful development of a high-performance, thermally stable, and magnetically responsive nanocomposite with broad potential applications in environmental remediation, biomedical engineering, and advanced material systems.

Introduction: This work aims to develop an eco-friendly, plant-based synthesis of silver nanoparticles using Citrullus colocynthis to combat Scopulariopsis alboflavescens. The approach addresses the need for alternative antifungal treatments and reduces the environmental impact of conventional methods. It offers a sustainable solution by utilizing the plant’s medicinal properties in nanotechnology applications. Method: Biomimetic synthesis of silver nanoparticles (AgNPs) was prepared by seed, fruit pulp crude methanolic extract of a medicinal plant Citrullus colocynthis (Linn.) Schrad exhibited the potential effect to inhibit the growth of the fungus (Scopulariopsis alboflavescens) isolated from the Juniper tree from Ziarat, Pakistan. The shape, size, specific surface area, charge, and composition of the silver nanoparticles were studied by UV-visible spectroscopy, infra-red spectroscopy, x-ray diffraction technique, and atomic force microscopy. Result: UV-visible spectrum of AgNPs displayed the surface plasmon resonance (SPR) peak at (427nm), and Fourier transform infra-red (FTIR) spectrum revealed the possible presence of polyphenols and alkaloids involved in the synthesis, capping, and stabilizing of AgNPs. Furthermore, X-ray diffraction (XRD) analysis showed face centered cubic (FCC) shape of AgNPs. Atomic force microscopic (AFM) analysis showed poly dispersion of AgNPs with a size of 28.8nm. The AgNPs exhibited a significant inhibitory zone of 22.5 mm against Scopulariopsis alboflavescens as compared to the standard with an inhibition zone of 7.5 mm at 1000 ppm, the biosynthesized AgNPs might be an effective strategy to control these pathogenic fungi and combat fungal diseases. Conclusion: The findings focus on the efficiency of Cc-AgNPs against S. alboflavescens of plant-pathogenic fungus and support to develop new and more active therapeutic substitutes for fungus diseases.

INTRODUCTION:Prolyl-specific oligopeptidase (POP), one of the brain's highly expressed enzymes, is an important target for the therapy of central nervous system disorders, notably autism spectrum disorder, schizophrenia, Parkinson's, Alzheimer's disease, and dementia. METHODS:The current study was designed to investigate 2,4-bis(trifluoromethyl) benzaldehyde- based thiosemicarbazones as POP inhibitors to treat the above-mentioned disorders. A variety of techniques, such as nuclear magnetic resonance (NMR), mass spectrometry (MS), and Fourier-transform infrared spectroscopy (FTIR), were used for the structural confirmation of synthesized compounds. After in vitro evaluation, all of these compounds were found to be prominent inhibitors of the POP enzyme (IC50= 10.14 - 41.73 μM). RESULTS:Compound 3a emerged as the most active compound (IC50 10.14 ± 0.72 μM) of the series. The kinetic study of the most active 3a (Ki =13.66 0.0012 μM) indicated competitive inhibition of the aforementioned enzyme. CONCLUSION:Moreover, molecular docking depicted a noticeable role of thiosemicarbazide moiety in the binding of these molecules within the active site of the POP enzyme.

In the current work, a new series of novel Δ2-pyrazoline-1H-1,2,3-triazole derivatives (6a-6j and 7a-7f) were synthesized, followed by in situ biological evaluation to assess their antiproliferative and immunomodulatory potential against breast cancer cells (MDA-MB-231 and MCF-7), HUVECs, and PBMCs. The compounds demonstrated antiproliferative effects with IC50 values ranging from 116.92 to 549.73 µM. Seven compounds (6c, 6f, 6h, 6i, 7b, 7e, and 7f) exhibited promising antiproliferative activities with IC50 values below 140 µM in both MDA-MB-231 and MCF-7 cancer cell lines. Compound 7f demonstrated the highest antiproliferative effect with IC50 values of 116.92 µM in MDA-MB-231 and 124.72 µM in MCF-7, with an acceptable cytotoxicity profile in normal HUVEC cells (IC50 = 208.41 µM); thus, immunomodulatory effects of 7f on checkpoint signaling were further evaluated. Compound 7f showed a dose-dependent increase of TIGIT, PD-1, and LAG-3 expression in CD3+ T cells. These changes may enhance responsiveness to checkpoint-targeted therapies while reflecting complex regulation of T-cell function. In silico target fishing and molecular docking reflect calpain as a probable target for 7f, while DFT analysis indicates electrophilic and nucleophilic positions within 7f may help its interaction with the target. Molecular dynamics (MD) simulation supports strong binding of 7f with binding energy (-22.259 ± 4.71 kcal mol-1).

Salmonella Paratyphi A (SPA) causing paratyphoid fever, a significant health concern in South Asia, particularly in Pakistan. This research aimed to explore the antibiotic resistance pattern, genetic diversity, and the evolutionary dynamics of SPA isolated from suspected paratyphoid patients in Pakistan. Whole-genome sequencing (WGS) of (n = 10) isolates predicted predominantly serotype O-2, H1: a, H2:1,5. Sequence type (ST85) was detected, alongside three STs (ST21eb, ST6d3b, ST95c4) and eight pathogenicity islands. The study reported extensively drug resistant (XDR) isolates (SPA 2,14,27,79) as per the AMR genes detected in IncY and IncQ1 plasmids (blaTEM-1, blaCTX-M-15, sul1, sul2, dfrA7, catA1, qnrS1) along with multiple resistance associated mutations in gyrA (S83F, E133G), gyrB (T14M), ParC (T57S) and AcrB (L40P) genes. These genomic results were co-related with phenotypic resistance exhibited by XDR Paratyphi A isolates against different class of antibiotics. The Paratyphi A strains (SPA 1,2,14,27 and 79) harbored highest number of unique genes determined by pangenome analysis. Interestingly these strains were highly virulent and exhibited XDR profile which indicated significant resistance and virulence genes transfer through horizontal gene transfer mechanism. The phylogenetic Tree constructed by maximum likelihood method showed that eight of the ten SPA isolates of the study belonged to genotype 2.3 as they formed a tight cluster with reference strain (AKU_12601). The present study represents a well-characterized genomic profiling of Salmonella Paratyphi A isolates from Pakistan. The detection of XDR alarms the situation in the country as no XDR reported yet in Paratyphi A. Unavailability of vaccines for Paratyphi A strains further warns of limited treatment and prevention strategies thus possess serious public health threat. The findings emphasize the need for urgent action by public health authorities to mitigate the potential emerging XDR Salmonella Paratyphi A and prevent its future outbreaks in Pakistan.

INTRODUCTION:Several pathological conditions, including glaucoma, malignant brain tumors, and renal, gastric, and pancreatic carcinomas, are commonly associated with carbonic anhydrase type II (CA-II). Additionally, CA-II plays a critical role in regulating bicarbonate concentration in the eyes. The inhibition of CA-II reduces aqueous humor production and thus lowers intraocular pressure associated with glaucoma. OBJECTIVES:This study aimed to synthesize potent CA-II inhibitors, 5-nitro-1H-benzo[ d]imidazole-2(3H)-thione (5NBIT) and acylhydrazone derivatives (1-13). METHODS:In this study, a new series of potent CA-II inhibitors, 5-nitro-1H-benzo[d]imidazole- 2(3H)-thione (5NBIT) and acylhydrazone derivatives (1-13), were synthesized and characterized by IR, NMR, UV and mass spectroscopy and evaluated against bovine carbonic anhydrase-II (bCA-II). RESULTS:Interestingly, most of the compounds showed better inhibition than the standard drug, acetazolamide (IC50: 18.2±0.51 μM), such as compounds 1 (IC50: 10.5±0.81 μM), 2 (IC50: 11.3±0.36 μM), 3 (IC50: 16.5±0.53 μM), 4 (IC50: 15.8±1.02 μM), 5 (IC50: 13.7±1.03 μM), and 9 (IC50: 12.2±1.03 μM). Among the synthesized compounds, compound 7 (IC50: 8.2±0.32 μM) exhibited the highest and compound 6 (IC50: 27.6±0.39 μM) showed the lowest inhibition. Structure-activity relationships suggest that the presence of nitro group on the phenyl ring contributed significantly to the overall inhibitory activity. Molecular docking of all the active compounds was performed to predict their binding behavior, which indicated good agreement between docking and experimental findings. Moreover, the MD simulation of compound 7 also showed excellent binding behavior and binding energy within the binding cavity of bCA-II. CONCLUSION:These findings suggest that the synthesized 5NBIT and acylhydrazone derivatives exhibited potent CA-II inhibition, with several compounds outperforming the standard drug acetazolamide. These results provide valuable insights for the development of novel CA-II inhibitors with potential therapeutic applications in glaucoma and other related conditions.

BACKGROUND:Aerobic glycolysis is crucial for cancer cells to survive, grow, and progress. In the current study, the anti-cancer effects of astragalin (ASG) on breast cancer cells and in the glycolytic pathway through AMPK/mTOR have been evaluated. OBJECTIVE:The objective of this study was to examine the impact of ASG, a natural flavonoid, on glycolysis via targeting AMPK/mTOR signalling in MDA-MB-231 breast cancer cells. METHODS:The study utilized ASG, which was isolated from Haplophyllum tuberculatum. The cells were treated with different concentrations of ASG (20 and 40 μg/mL), and anti-glycolytic activities were measured through cell proliferation, expression of glycolytic enzymes (HK-2, LDH-A, GLUT-1), glucose uptake, and lactate concentration assays. The MTT assay was used to assess cellular proliferation, while the glucose uptake and lactate levels were determined by employing colorimetric assays. The mRNA expression of target glycolytic enzymes was determined by qRT-PCR. The protein levels of glycolytic targets, as well as that of AMPK and mTOR, were determined by western blot. in silico docking of ASG was done with mTOR and AMPK proteins. RESULTS:Astragalin exhibited dose- and time-dependent anti-proliferative effects in MDA-MB-231 cells. In breast cancer cells, the mRNA and protein expression of GLUT-1, LDH-A, and HK-2 were all significantly downregulated after receiving ASG treatments. Furthermore, after ASG treatments, MDA-MB231 cells showed a significant decrease in lactate and glucose uptake compared to control cells. Mechanistically, ASG increased AMPK activation and suppressed mTOR activation in these cells. The inhibitory role of ASG on aerobic glycolysis was prevented by treatments with compound C (an AMPK inhibitor). However, combined treatment of compound C and ASG could nullify the ASG-induced anti-glycolysis effect and restore the level of p-AMPK and p-mTOR in MDA-MB231 cells. The results from molecular docking predicted that ASG had the potential to bind AMPK and mTOR, with free energy for binding, -8.2 kcal/mol and -8.1 kcal/mol, respectively. CONCLUSION:Taken together, the findings from this study indicated that ASG might modulate the AMPK/mTOR pathway to inhibit aerobic glycolysis and proliferation of MDAMB231 breast cancer.

Diabetes mellitus has dominated the globe as a chronic health condition and has become a major global health concern. The inhibition of the key metabolic enzymes of carbohydrates digestion including α-amylase and α-glucosidase are the promising targets for the treatment of diabetes via delaying glucose absorption. Therefore, nitrogen containing saturated heterocycle (pyrrolidinyl, piperidinyl and N-methylpiperazinyl) based hydrazones derivatives 5-23 were synthesized through two step reactions and evaluated for their anti-diabetic potential. All compounds exhibited potent α-glucosidase inhibitory capability ranging (IC50 = 10.26-47.35 µM), as compared to acarbose (IC50 = 871.40 ± 1.24 µM). Interestingly these derivatives also exhibited significant inhibitory capability against α-amylase with IC50 values in the range 25.81-76.05 µM. Mechanistic study on the most potent compound indicated a competitive type of inhibition with a Ki value of 8.30 ± 0.0076 µM. Molecular docking was performed to predict binding interactions between receptor proteins and moiety. In QSAR analysis, through use of QSARINS different 1D and 2D descriptors were used to generate different models that enabled further identification of structural requirements that contributed to activity. pIC50 values were also predicted by QSAR model. Furthermore, in-silico ADMET and BOILED-egg model analysis showed that all analogues exhibited passive GI absorption, and all showed BBB penetration.

This study explores the floristic and ethnobotanical diversity of Bagh Valley, highlighting the significance of local plant species in traditional medicine. Over two years (2019-2020), we documented 88 plant species from 44 families, with 29 trees, 48 herbs, and 11 shrubs. Notably, most of these plants are wild and freely available, yet play a vital role in treating various ailments, including cough, malaria, kidney disease, and diabetes, among others.Our research reveals that local communities rely heavily on these plants, utilizing different parts, such as leaves (14.77%), fruits (21.59%), seeds (5.68%), and whole plants (20.45%), to harness their medicinal properties. Key medicinal plants include _Myrtus communis_, _Carolluma tuberculata_, _Justicia adhatoda L_, _Olea ferrugina Royle_, and _Ocimum bascillicum_. This study underscores the importance of preserving traditional knowledge and promoting sustainable use of these valuable plant resources.

In this present work, we describe the syntheses of a new series of 32 1H-indole-based-meldrum linked 1H-1,2,3- triazole derivatives (2-13, 15a-15f, 16a- 16f, 17a- 17f and 19a, 19b, 20a ), which constitute a new class of 1H- 1,2,3-triazoles. Compounds 15a-15f, 16a- 16f, 17a- 17f have been prepared by employing "click" reactions between substituted 1H-indole-based meldrum alkynes (11, 12 and 13 ) and substituted aromatic azides ( 14a-14f) in the presence of copper iodide (CuI) and H & uuml;nig's base. Then, the synthesis of compounds 19 , 20 through decomposition of meldrum moiety. The resulting compounds have been screened for their dihydrofolate reductase (DHFR) inhibition activity. All the newly synthesized compounds were characterized by 1 H NMR, 13C NMR, 19 F NMR (spectroscopy when applicable), and HR-ESI-MS spectroscopy techniques. The X-ray crystallography studies have unambiguously confirmed the structure of compounds 6 , 11 and 13 . Furthermore, their DHFR-inhibitory activity was evaluated in-vitro. The results obtained from the DHFR-inhibitory assay revealed that all the synthesized 1H-indole-based-meldrum linked 1H-1,2,3-triazole derivatives were highly potent inhibitors, with IC50 values in the range 3.48 +/- 0.16-30.37 +/- 1.20 mu M. Ten compounds ( 15c-15f, 16c-16f, 17e and 17f) among the 32 synthesized 1H-indole-based-meldrum linked 1H-1,2,3-triazole compounds were found to exhibit exceptional inhibitory while the rest of the derivatives showed moderate activities. Additionally, molecular docking analysis of the most active (16f), moderate (15c) and least active (16a) inhibitors reflect excellent binding of 16f with the binding residues of DHFR with higher docking score (-9.13 kcal/mol) than that of 15c and 16a. The docking analysis correlates well with the inhibitory potential of these synthesized molecules. Overall, this study may pave the way to medicinal analogues of 1H-indole-based-meldrum linked 1H-1,2,3-tri- azoles as potent DHFR inhibition activity.