A systematic review on understanding the mechanistic pathways and clinical aspects of natural CDK inhibitors on cancer progression.: Unlocking cellular and biochemical mechanisms.

Cell division, differentiation, and controlled cell death are all regulated by phosphorylation, a key biological function. This mechanism is controlled by a variety of enzymes, with cyclin-dependent kinases (CDKs) being particularly important in phosphorylating proteins at serine and threonine sites. CDKs, which contain 20 unique components, serve an important role in regulating vital physiological functions such as cell cycle progression and gene transcription. Methodologically, an extensive literature search was performed using reputable databases such as PubMed, Google Scholar, Scopus, and Web of Science. Keywords encompassed "cyclin kinase," "cyclin dependent kinase inhibitors," "CDK inhibitors," "natural products," and "cancer therapy." The inclusion criteria, focused on relevance, publication date, and language, ensured a thorough representation of the most recent research in the field, encompassing articles published from January 2015 to September 2023. Categorization of CDKs into those regulating transcription and those orchestrating cell cycle phases provides a comprehensive understanding of their diverse functions. Ongoing clinical trials featuring CDK inhibitors, notably CDK7 and CDK4/6 inhibitors, illuminate their promising potential in various cancer treatments. This review undertakes a thorough investigation of CDK inhibitors derived from natural (marine, terrestrial, and peptide) sources. The aim of this study is to provide a comprehensive comprehension of the chemical classifications, origins, target CDKs, associated cancer types, and therapeutic applications.

Molecular modeling of novel 2-aminopyridine derivatives as potential JAK2 inhibitors: a rational strategy for promising anticancer agents.

Janus kinase 2(JAK2) is a potential target for anticancer drugs in the treatment of numerous myeloproliferative diseases due to its central role in the JAK/STAT signaling cascade. In this study, the binding behavior of 2 amino-pyridine derivatives as JAK2 inhibitors was investigated by using multifaceted strategies including 3D-QSAR, molecular docking, Fingerprint analysis, MD simulations, and MM-PBSA calculations. A credible COMFA (q2 = 0.606 and r2 = 0.919) and COMSIA (q2 = 0.641 and r2 = 0.992) model was developed, where the internal and external validation revealed that the obtained 3D-QSAR models could be capable of predicting bioactivities of JAK2 inhibitors. The structural criteria provided by the contour maps of model were used to computationally develop more potent 100 new JAK2 inhibitors. Docking studies were conducted on the model data set and newly developed compounds (in-house library) to demonstrate their binding mechanism and highlight the key interacting residues within JAK2 active site. The selected docked complexes underwent MD simulation (100 ns), which contributed in the further study of the binding interactions. Binding free energy analyses (MMGB/PBSA) revealed that key residues such as Glu930, Leu932 (hinge region), Asp939 (solvent accessible region), Arg980, Asn981and Asp994 (catalytic site) have a significantly facilitate ligand-protein interactions through H-bonding and van der Waals interactions. The preliminary in-silico ADMET evaluation revealed encouraging results for all the modeled and in-house library compounds. The findings of this research have the potential to offer valuable recommendations for the advancement of novel, potent, and efficacious JAK2 inhibitors. Overall, this work has successfully employed a wide range of computer-based methodologies to understand the interaction dynamics between 2-amino-pyridine derivatives and the JAK2 enzyme, which is a crucial target in myeloproliferative disorders.Communicated by Ramaswamy H. Sarma.

Biochemical, Toxicological, and in Silico Aspects of Trillium govanianum Wall. ex D.Don (Trilliaceae): A Rich Source of Natural Bioactive Compounds.

Trillium govanianum is a high-value medicinal herb, having multifunctional traditional and culinary uses. The present investigation was carried out to evaluate the phytochemical, biological and toxicological parameters of the T. govanianum Wall. ex D. Don (Family: Trilliaceae) roots collected from Azad Kashmir, Pakistan. Phytochemical profiling was achieved by determining total bioactive contents (total phenolic and flavonoid contents) and UHPLC-MS analysis. For biological evaluation, antioxidant activities (DPPH, ABTS, FRAP, CUPRAC, phosphomolybdenum, and metal chelation assays) and enzyme inhibition activities (against AChE, BChE, glucosidase, amylase, and tyrosinase) were performed. Moreover, cytotoxicity was assessed against three human carcinoma cell lines (MDA-MB-231, CaSki, and DU-145). The tested extract was found to contain higher total phenolics (7.56 mg GAE/g dry extract) as compared to flavonoid contents (0.45 mg RE/g dry extract). Likewise, for the antioxidant activity, higher CUPRAC activity was noted with 39.84 mg TE/g dry extract values. In the case of enzyme assays, higher activity was pointed out against the cholinesterase, glucosidase and tyrosinase enzymes. The plant extract displayed significant cytotoxicity against the cell lines examined. Moreover, the in-silico studies highlighted the interaction between the important phytochemicals and tested enzymes. To conclude, the assessed biological activity and the existence of bioactive phytochemicals in the studied plant extract may pave the way for the development of novel pharmaceuticals.

3D-QSAR, docking and molecular dynamics simulations of novel Pyrazolo-pyridazinone derivatives as covalent inhibitors of FGFR1: a scientific approach for possible anticancer agents.

Developing highly potent covalent inhibitors of Fibroblast growth factor receptors 1 (FGFR1) has always been a challenging task. In the current study, various computational techniques, such as 3D-QSAR, covalent docking, fingerprinting analysis, MD simulation followed by MMGB/PBSA, and per-residue energy decomposition analysis were used to explore the binding mechanism of pyrazolo[3,4-d]pyridazinone derivatives to FGFR1. The high q2 and r2 values for the CoMFA and CoMSIA models, suggest that the constructed 3D-QSAR models could reliably predict the bioactivities of FGFR1 inhibitors. The structural requirements revealed by the model's contour maps were strategically used to computationally create an in-house library of more than 100 new FGFR1 inhibitors using the R-group exploration technique implemented in the SparkTM software. The compounds from the in-house library were also mapped in the 3D-QSAR model that predicts comparable pIC50 values with the experimental values. A comparison between 3D-QSAR generated contours and molecular docking conformation of ligands was performed to reveal the fundamentals to design potent FGFR1 covalent inhibitors. The estimated binding free energies (MMGB/PBSA) for the selected compounds were in agreement with the experimental value ranking of their binding affinities towards FGFR1. Furthermore, per-residue energy decomposition analysis has identified Arg627 and Glu531 to contribute significantly in improved binding affinity of compound W16. During ADME analysis, the majority of in-house library compounds exhibited pharmacokinetic properties superior to those of experimentally produced compounds. These new compounds may help researchers better understand FGFR1 inhibition and lead to the creation of novel, potent FGFR1 inhibitors.Communicated by Ramaswamy H. Sarma.

Integrated computational approaches for designing potent pyrimidine-based CDK9 inhibitors: 3D-QSAR, docking, and molecular dynamics simulations.

CDK9 is an emerging target for the development of anticancer drugs. The development of CDK9 inhibitors with significant potency had consistently posed a formidable challenge. In the current research, a number of computational methodologies, such as, 3D-QSAR, molecular docking, fingerprint analysis, molecular dynamic (MD) simulations followed by MMGB/PBSA and ADMET studies were used systemically to uncover the binding mechanism of pyrimidine derivatives against CDK9. The CoMFA and CoMSIA models having high q2 (0.53, 0.54) and r2 values (0.96, 0.93) respectively indicating that model could accurately predict the bioactivities of CDK9 inhibitors. Using the R-group exploration technique implemented by the Spark™ by Cresset group, the structural requirements revealed by the contour maps of model were utilized strategically to create an in-house library of 100 new CDK9 inhibitors. Additionally, the compounds from the in-house library were mapped into 3D-QSAR model which predicted pIC50 values comparable to the experimental values. A comparison between 3D-QSAR generated contours and molecular docking conformation of ligands was performed to elucidate the essentials of CDK9 inhibitor design. MD simulations (100 ns) were performed on the selected docked complexes A21, A14 and D98 which contributed in validating the binding interactions. According to the findings of binding free energy analysis (MMGB/PBSA), It was observed that residues CYS106 and GLU107 had a considerable tendency to facilitate ligand-protein interactions via H-bond interactions. The aforementioned findings have the potential to enhance researchers comprehension of the mechanism underlying CDK9 inhibition and may be utilized in the development of innovative and efficacious CDK9 inhibitors.

Nutritional and medicinal plants as potential sources of enzyme inhibitors toward the bioactive functional foods: an updated review.

Enzymes are biologically active complex protein molecules that catalyze most chemical reactions in living organisms, and their inhibitors accelerate biological processes. This review emphasizes medicinal food plants and their isolated chemicals inhibiting clinically important enzymes in common diseases. A mechanistic overview was investigated to explain the mechanism of these food bases enzyme inhibitors. The enzyme inhibition potential of medicinal food plants and their isolated substances was searched in Ovid, PubMed, Science Direct, Scopus, and Google Scholar. Cholinesterase, amylase, glucosidase, xanthine oxidase, tyrosinase, urease, lipoxygenase, and others were inhibited by crude extracts, solvent fractions, or isolated pure chemicals from medicinal food plants. Several natural compounds have shown tyrosinase inhibition potential, including quercetin, glabridin, phloretin-4-O-ß-D-glucopyranoside, lupinalbin, and others. Some of these compounds' inhibitory kinetics and molecular mechanisms are also discussed. Phenolics and flavonoids inhibit enzyme activity best among the secondary metabolites investigated. Several studies showed flavonoids' significant antioxidant and anti-inflammatory activities, highlighting their medicinal potential. Overall, many medicinal food plants, their crude extracts/fractions, and isolated compounds have been studied, and some promising compounds depending on the enzyme have been found. Still, more studies are recommended to derive potential pharmacologically active functional foods.

Exploring the Potent Combination of Quercetin-Boronic Acid, Epalrestat, and Urea Containing Nanoethosomal Keratolytic Gel for the Treatment of Diabetic Neuropathic Pain: In Vitro and In Vivo Studies.

Transdermal penetration of therapeutic moieties from topical dosage forms always remains a challenge due to the presence of permeation impeding keratin which should be addressed. The purpose of the study was to formulate quercetin and 4-formyl phenyl boronic acid (QB complex) used for the preparation of nanoethosomal keratolytic gel (EF3-G). The QB complex was confirmed by Fourier transform infrared spectroscopy while skin permeation, viscosity, and epalrestat entrapment efficiency were used for the optimization of nanoethosomal gel. The keratolytic effect of the proposed nanoethosomal gel with urea (QB + EPL + U) was calculated in rat and snake skin. The spherical shape of nanoethosomes was confirmed by scanning electron microscopy. According to the findings of stability studies, viscosity decreases as temperature increases, proving their thermal stability. The negative charge of optimized EF3 with 0.7 PDI proved narrow particle size distribution with homogeneity. Optimized EF3 showed two folds increase of epalrestat permeation in highly keratinized snake skin as compared to rats' skin after 24 h. Antioxidant behaviors of EF3 (QB) > QB complex > quercetin > ascorbic acid proved reduction of oxidative stress in DPPH reduction analysis. Interestingly, the hot plate and cold allodynia test in the diabetic neuropathic rat model reduced 3-fold pain as compared to the diabetic control group which was further confirmed by in vivo biochemical studies even after the eight week. Conclusively, ureal keratolysis, primary dermal irritation index reduction, and improved loading of epalrestat render the nanoethosomal gel (EF3-G) ideal for the treatment of diabetic neuropathic pain.

Green synthesis and characterization of silver nanoparticles through the Piper cubeba ethanolic extract and their enzyme inhibitory activities.

Introduction: The area of "Green Synthesis of Nano-medicine," as compared to its synthetic counterparts, is a relatively safer research technology for various biomedical applications, including identification, therapeutic application, and prevention of pathological conditions, pain control, safety, and development of human wellness. The present study explored the synthesis and characterization of AgNPs using the ethanolic extract of Piper cubeba fruit as a reducing and stabilizing agent and its potential as an enzyme inhibitory agent. Urease inhibitors are helpful against many severe diseases, including gastric ulcers induced by Helicobacter pylori. Method: The fruits of the Piper cubeba plant were taken and ground to a fine powder. Plant material was added to 500 ml ethanol, and the mixture was filtered. The solvent of the filtrate was evaporated, and a thick, gummy extract was obtained and stored at 4°C in the refrigerator. AgNPs were green synthesized from solutions of AgNO3 using the P. cubeba extract, which was indicated by a change in the color from light brown to deep brown. The synthesized AgNPs were characterized via Ultraviolet-visible (UV-Vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), and scanning electron microscopy (SEM). Results and Discussion: Analysis showed the reduction of Ag+ to Ag0 at room temperature (25°C), and the average particle size of AgNPs was in the range of 40-80 nm. Consequently, the synthesized AgNPs were evaluated for their anti-urease activity. The maximum urease inhibition of the Piper cubeba ethanolic extract was 88.5% at 5 mg conc., and of derived nanoparticles was 78.6% at 0.05 mg conc. The results were nearly similar to the control drug, i.e., thiourea (0.5 and 0.6 mM conc., respectively). Conclusion: The study concluded that the P. cubeba extract, as well as its green-derived AgNPs, might prove to be a better and safer substitute for their enzyme inhibitory potential in emerging medicine and novel drug delivery techniques to improve and maintain human health.

Molecular modeling of pyrrolo-pyrimidine based analogs as potential FGFR1 inhibitors: a scientific approach for therapeutic drugs.

Fibroblast growth factor receptors 1 (FGFR1) is an emerging target for the development of anticancer drugs. Uncontrolled expression of FGFR1 is strongly associated with a number of different types of cancers. Apart from a few FGFR inhibitors, the FGFR family members have not been thoroughly studied to produce clinically effective anticancer drugs. The application of proper computational techniques may aid in understanding the mechanism of protein-ligand complex formation, which may provide a better notion for developing potent FGFR1 inhibitors. In this study, a variety of computational techniques, including 3D-QSAR, flexible docking and MD simulation followed by MMGB/PBSA, H-bonds and distance analysis, have been performed to systematically explore the binding mechanism of pyrrolo-pyrimidine derivatives against FGFR1. The 3D-QSAR model was generated to deduce the structural determinants of FGFR1 inhibition. The high q2 and r2 values for the CoMFA and CoMSIA models indicated that the created 3D-QSAR models could reliably predict the bioactivities of FGFR1 inhibitors. The computed binding free energies (MMGB/PBSA) for the selected compounds were consistent with the ranking of their experimental binding affinities against FGFR1. Furthermore, per-residue energy decomposition analysis revealed that the residues Lys514 in catalytic region, Asn568, Glu571 in solvent accessible portion and Asp641 in DFG motif exhibited a strong tendency to mediate ligand-protein interactions through the hydrogen bonding and Van Der Waals interactions. These findings may benefit researchers in gaining better knowledge of FGFR1 inhibition and may serve as a guideline for the development of novel and highly effective FGFR1 inhibitors.Communicated by Ramaswamy H. Sarma.

A Comprehensive Approach to Derivatization: Elemental Composition, Biochemical, and In Silico Studies of Metformin Derivatives Containing Copper and Zinc Complexes.

The current study was designed to synthesize, characterize, and screen the molecular and biological activities of different metformin derivatives that possess potent antidiabetic potential with minimal side-effects. Metformin-based derivatives containing the metal complexes Cu II (MCu1-MCu9) and Zn II (MZn1-MZn9) were generated using aromatic aldehydes and ketones in a template process. The novel metal complexes were characterized through elemental analysis, physical state, melting point, physical appearance, Fourier-transform infrared (FTIR) spectroscopy, UV/visible (UV/Vis) spectroscopy, 1H nuclear magnetic resonance (NMR) spectroscopy, and 13C-NMR spectroscopy. Screening for inhibitory activity against the enzymes α-amylase and α-glucosidase, and molecular simulations performed in Schrödinger were used to assess the synthesized derivatives' biological potential. Met1, Met2, Met3, and Met8 all displayed activities that were on par with the reference in an enzymatic inhibition assay (amylase and glucosidase). The enzyme inhibition assay was corroborated by molecular simulation studies, which also revealed a competitive docking score compared to the gold standard. The Swiss ADME online web server was utilized to compute ADME properties of metformin analogues. Lipinski's rule of five held true across all derivatives, making it possible to determine the percentage of absorption. Metformin derivatives showed significant antidiabetic activities against both targeted enzymes, and the results of this work suggest that these compounds could serve as lead molecules for future study and development.

Comparative phytochemical composition, oleuropein quantification, antioxidant and cytotoxic properties of Olea europaea L. leaves.

In the present research, oleuropein (OLE) contents from two Saudi Arabian wild olive trees (Olea europaea L.) leaves (O1 and O2), were collected from two nearby geographical sites differing in altitudes, and were determined via UHPLC-MS analysis. Moreover, total bioactive contents, antioxidant, and cytotoxicity (against MCF-7 and MDA-MB-231 cells) potential were also evaluated. The sample (O2) was found to contain significantly (p < 0.05) higher OLE content (4.13 ± 1.0 mg/g DW) compared with the sample (O1) having OLE content (3.63 ± 1.1 mg/g DW). A similar trend was observed regarding total bioactive contents and antioxidant potential. However, both samples exhibited low cytotoxicity against tested cell lines. Furthermore, with hierarchical cluster analysis that compared the results of our samples (O1 and O2) to other samples reported in the literature, it was found that the variance in OLE content and biological activities from Al Baha region leaves had a resemblance to other reported superior cultivars.

Phytochemical profiling, in vitro biological activity, docking studies, and cytotoxicity assessments of Rondeletia odorata Jacquin: An unexplored plant of the coffee family.

Rondeletia odorata Jacquin is a flowering plant that belongs to the coffee family. As a rich source of polyphenols with significant antioxidant potential, R. odorata may have health benefits. Therefore, in the current work, ethanolic extract of aerial parts and its n-hexane, ethyl acetate, and n-butanol soluble fractions were analyzed for their antioxidant potential and various enzyme inhibition properties. The total phenolic and flavonoid contents of the crude ethanol extract (ROE) and its n-hexane (ROH), ethyl acetate (ROEA), and n-butanol (ROB) fractions were determined spectrophotometrically, while metabolic profiling was established through UHPLC-MS analysis, which revealed the presence of 58 phytochemicals. Total phenolic and flavonoid contents of ROE extract were measured as 51.92 mg GA.Eq./g of dry extract and 52.35 mg Qu.Eq./g of the dry extract, respectively. In the DPPH radical scavenging activity assay, ROE and ROEA showed the highest potential with values of 62.13 ± 0.62 and 76.31% ± 1.86%, respectively, comparable to quercetin (80.89% ± 0.54%). Similarly, in the FRAP assay, the same pattern of the activity was observed with ROE and ROEA, which displayed absorbance values of 1.32 ± 0.01 and 0.80 ± 0.02 at 700 nm, respectively, which are comparable (1.76 ± 0.02) with the reference compound quercetin, whereas the ROH showed maximum metal-chelating capacity (62.61% ± 1.01%) among all extracts and fractions. Antibacterial activity assay indicated that the ROEA fraction was the most active against Serratia marcescens, Stenotrophomonas maltophilia, Bacillus subtilis, Klebsiella pneumonia, and Staphylococcus aureus, while the rest of the fractions showed good to moderate activity. Enzyme inhibition assays showed that ROEA fraction exhibited the highest activity with IC50 values of 2.78 ± 0.42 and 3.95 ± 0.13 mg/mL against urease and carbonic anhydrase (CA), respectively. Furthermore, the docking studies of some of the major compounds identified in the extract revealed a strong correlation with their inhibitory activity. All extracts and fractions were also tested for their thrombolytic activity, and the ROB fraction showed a notable potential. Antiviral assay led to remarkable outcomes. Thus, it can be inferred that aerial parts of R. odorata are potential sources of bioactive components with several significant pharmacological activities.

Synthesis, characterization, molecular docking and biological evaluation of Schiff Base derivatives of cefpodoxime.

Synthesis of new Cefpodoxime derivatives via Schiff Bases mechanism and the efficiency of their antimicrobial and antiviral activities were addressed. They were analyzed for structural validation by using spectroscopic techniques using FTIR, 1HNMR, and 13CNMR. Molecular docking against IBV Virus papain-like protease (PLPro) was done with Auto dock tools against compounds having excellent IC50 values against IBV (Corona Class) virus. All derivatives showed strong zone of inhibition ranges from (55 ± 2.0 to 70 ± 0.8 mm) against E. coli. Compounds 1,2,4 and 6 derivatives showed remarkable activity against Stenotrophomonas maltophilia and Serratia marcescens. But For most the newly synthesized derivatives C 1 (64 ± 1.60), C 3 (32 ± 0.80), and C 8 (64 ± 1.60) showed potential IC50 values against two variants of Corona class viruses i.e. Avian Influenza (H9) and Avian corona (IBV) viruses. The current study revealed that newly synthesized Schiff Bases possessed strong anti-viral potential. Further studies may make a breakthrough in medical sciences to tackle latest challenges such as Corona Virus Diseases.

Metabolic Profiling by GC-MS, In Vitro Biological Potential, and In Silico Molecular Docking Studies of Verbena officinalis.

Verbena officinalis L. is a traditionally important medicinal herb that has a rich source of bioactive phytoconstituents with biological benefits. The objective of this study was to assess the metabolic profile and in vitro biological potential of V. officinalis. The bioactive phytoconstituents were evaluated by preliminary phytochemical studies, estimation of polyphenolic contents, and gas chromatography-mass spectrometry (GC-MS) analysis of all fractions (crude methanolic, n-hexane, ethyl acetate, and n-butanol) of V. officinalis. The biological investigation was performed by different assays including antioxidant assays (DPPH, ABTS, CUPRAC, and FRAP), enzyme inhibition assays (urease and α-glucosidase), and hemolytic activity. The ethyl acetate extract had the maximum concentration of total phenolic and total flavonoid contents (394.30 ± 1.09 mg GAE·g-1 DE and 137.35 ± 0.94 mg QE·g-1 DE, respectively). Significant antioxidant potential was observed in all fractions by all four antioxidant methods. Maximum urease inhibitory activity in terms of IC50 value was shown by ethyl acetate fraction (10 ± 1.60 µg mL-1) in comparison to standard hydroxy urea (9.8 ± 1.20 µg·mL-1). The n-hexane extract showed good α-glucosidase inhibitory efficacy (420 ± 20 µg·mL-1) as compared to other extract/fractions. Minimum hemolytic activity was found in crude methanolic fraction (6.5 ± 0.94%) in comparison to positive standard Triton X-100 (93.5 ± 0.48%). The GC-MS analysis of all extract/fractions of V. officinalis including crude methanolic, n-hexane, ethyl acetate, and n-butanol fractions, resulted in the identification of 24, 56, 25, and 9 bioactive compounds, respectively, with 80% quality index. Furthermore, the bioactive compounds identified by GC-MS were analyzed using in silico molecular docking studies to determine the binding affinity between ligands and enzymes (urease and α-glucosidase). In conclusion, V. officinalis possesses multiple therapeutical potentials, and further research is needed to explore its use in the treatment of chronic diseases.

Comprehensive Biological Potential, Phytochemical Profiling Using GC-MS and LC-ESI-MS, and In-Silico Assessment of Strobilanthes glutinosus Nees: An Important Medicinal Plant.

Plants of the genus Strobilanthes have notable use in folklore medicines as well as being used for pharmacological purposes. The present work explored the biological predispositions of Strobilanthes glutinosus and attempted to accomplish a comprehensive chemical profile through GC-MS of different fractions concerning polarity (chloroform and n-butanol) and LC-ESI-MS of methanolic extract by both positive and negative ionization modes. The biological characteristics such as antioxidant potential were assessed by applying six different methods. The potential for clinically relevant enzyme (α-amylase, α-glucosidase, and tyrosinase) inhibition was examined. The DPPH, ABTS, CUPRAC, and FRAP results revealed that the methanol fraction presented efficient results. The phosphomolybdenum assay revealed that the n-hexane fraction showed the most efficient results, while maximum metal chelation potential was observed for the chloroform fraction. The GC-MS profiling of n-butanol and chloroform fractions revealed the existence of several (110) important compounds presenting different classes (fatty acids, phenols, alkanes, monoterpenes, diterpenes, sesquiterpenoids, and sterols), while LC-ESI-MS tentatively identified the presence of 44 clinically important secondary metabolites. The n-hexane fraction exhibited the highest potential against α-amylase (497.98 mm ACAE/g extract) and α-glucosidase (605.85 mm ACAE/g extract). Significant inhibitory activity against tyrosinase enzyme was displayed by fraction. Six of the prevailing compounds from the GC-MS study (lupeol, beta-amyrin, stigmasterol, gamma sitosterol, 9,12-octadecadienoic acid, and n-hexadecanoic acid) were modelled against α-glucosidase and α-amylase enzymes along with a comparison of binding affinity to standard acarbose, while three compounds identified through LC-ESI-MS were docked to the mushroom tyrosinase enzyme and presented with significant biding affinities. Thus, it is assumed that S. glutinosus demonstrated effective antioxidant and enzyme inhibition prospects with effective bioactive molecules, potentially opening the door to a new application in the field of medicine.

A comprehensive phytochemical, biological, and toxicological studies of roots and aerial parts of Crotalaria burhia Buch.-Ham: An important medicinal plant.

This study was designed to seek the phytochemical analysis, antioxidant, enzyme inhibition, and toxicity potentials of methanol and dichloromethane (DCM) extracts of aerial and root parts of Crotalaria burhia. Total bioactive content, high-performance liquid chromatography-photodiode array detector (HPLC-PDA) polyphenolic quantification, and ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) analysis were utilized to evaluate the phytochemical composition. Antioxidant [including 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH)], 2,2'-azino-bis[3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric reducing antioxidant power assay (FRAP), cupric reducing antioxidant capacity CUPRAC, phosphomolybdenum, and metal chelation assays] and enzyme inhibition [against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-glucosidase, α-amylase, and tyrosinase] assays were carried out for biological evaluation. The cytotoxicity was tested against MCF-7 and MDA-MB-231 breast cell lines. The root-methanol extract contained the highest levels of phenolics (37.69 mg gallic acid equivalent/g extract) and flavonoids (83.0 mg quercetin equivalent/g extract) contents, and was also the most active for DPPH (50.04 mg Trolox equivalent/g extract) and CUPRAC (139.96 mg Trolox equivalent /g extract) antioxidant assays. Likewise, the aerial-methanol extract exhibited maximum activity for ABTS (94.05 mg Trolox equivalent/g extract) and FRAP (64.23 mg Trolox equivalent/g extract) assays. The aerial-DCM extract was noted to be a convincing cholinesterase (AChE; 4.01 and BChE; 4.28 mg galantamine equivalent/g extract), and α-glucosidase inhibitor (1.92 mmol acarbose equivalent/g extract). All of the extracts exhibited weak to modest toxicity against the tested cell lines. A considerable quantities of gallic acid, catechin, 4-OH benzoic acid, syringic acid, vanillic acid, 3-OH-4-MeO benzaldehyde, epicatechin, p-coumaric acid, rutin, naringenin, and carvacrol were quantified via HPLC-PDA analysis. UHPLC-MS analysis of methanolic extracts from roots and aerial parts revealed the tentative identification of important phytoconstituents such as polyphenols, saponins, flavonoids, and glycoside derivatives. To conclude, this plant could be considered a promising source of origin for bioactive compounds with several therapeutic uses.

Protective Effects of p-CA Against Acute Liver Damage Induced by LPS/D-GalN in Wistar Albino Rats.

Aim: Liver regulates metabolism of biomolecules and injury of liver causes distortion of metabolic functions. This injury may be oxidative or inflammatory induced by numerous factors including alcohol, pathogens and xenobiotics. This scientific study was planned to investigate the anti-inflammatory and anti-oxidant potential of p-coumaric acid (p-CA) on Lipopolysaccharide/D-Galactosamine (LPS/D-GalN) induced liver injury. Methods: DPPH analysis, reducing power assay and HPLC analysis were performed during in-vitro studies of p-CA. Similarly, in-vivo experiments were performed using Wistar Albino rats. Normal control and intoxicated group received (5mL/kg normal saline p.o), standard treatment groups received ascorbic acid (100mg/kg p.o) and silymarin (25mg/kg p.o), while p-CA treatment groups received (100mg/kg p.o) for 28-days. After completion of 28-days, LPS/D-GalN injection (300 mg D-GalN/kg and 10 µg LPS/kg i.p.) was given at 6th, 12th and 24-hours to all groups except normal control group. Animals were sacrificed; serum and liver samples were harvested and subjected to biochemical and histological examinations, respectively. Results: The results revealed that p-CA possess strong antioxidant activity. Increased levels of leukocyte infiltration (TLC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBIL), lipid panel (eg TG, TC, LDL-C, VLDL-C), whereas decreased HDL-C levels noticed in LPS/D-GalN groups as compared to normal control groups. Pro-Inflammatory markers (eg TNF-α, IL-6, IL-1ß) and lipid peroxidation marker, eg malondialdehyde (MDA) increased while superoxide dismutase (SOD) and reduced glutathione (GSH) levels were decreased significantly in groups treated with LPS/D-GalN. ANOVA with Bonferroni post hoc analysis was used for statistical analysis of. H&E staining was done to assess architectural abnormalities among liver cells. Conclusion: In conclusion, p-CA could ameliorate LPS/D-GalN induced hepatic injury via regulation of immune responses, liver function enzymes, lipid profile, oxidative stress and pro-inflammatory markers.

Synthesis, biochemical characterization and in silico investigation of 3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid derivatives: dual action mode inhibitors of urease and virulent bacterial stains.

In the present work, we reported the synthesis of Schiff bases from 4-phenoxy-5-sulfamoylbenzoic acid motif. The reaction was carried out by substitution of different aldehyde and ketones at sulfamoyl group of sulfamoylbenzoic acid. The generated substituted products (4a-4i) possessed potent structure activity relationship and exhibited drug like properties. The structures of synthesized compounds were characterized on the basis of FT-IR, 1H NMR, 13C NMR and mass spectroscopic data. The effects of synthesized products were investigated on urease enzyme through anti-urease enzyme inhibition assay (Weather burn method). These compounds were further evaluated for antibacterial potential. The Rationale behind the assessment of antibacterial activity was to investigate the synthesized compound's dual mode action against urease and virulent bacterial strains in order to develop a lead candidate for the treatment of GIT diseases such as gastric and peptic ulcers, as well as hepatic encephalopathy. The synthesized derivatives have outstanding anti-urease and antibacterial action, as is evident from in vitro and in silico studies. As a result, these compounds (3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid; 4a-4i) might be explored further as a potential lead for the development of potent inhibitors in the future.

Multifaced Assessment of Antioxidant Power, Phytochemical Metabolomics, In-Vitro Biological Potential and In-Silico Studies of Neurada procumbens L.: An Important Medicinal Plant.

This work was undertaken to explore the phytochemical composition, antioxidant, and enzyme-inhibiting properties of Neurada procumbens L. extracts/fractions of varying polarity (methanol extract and its fractions including n-hexane, chloroform, n-butanol, and aqueous fractions). A preliminary phytochemical study of all extracts/fractions, HPLC-PDA polyphenolic quantification, and GC-MS analysis of the n-hexane fraction were used to identify the phytochemical makeup. Antioxidant (DPPH), enzyme inhibition (against xanthine oxidase, carbonic anhydrase, and urease enzymes), and antibacterial activities against seven bacterial strains were performed for biological investigation. The GC-MS analysis revealed the tentative identification of 22 distinct phytochemicals in the n-hexane fraction, the majority of which belonged to the phenol, flavonoid, sesquiterpenoid, terpene, fatty acid, sterol, and triterpenoid classes of secondary metabolites. HPLC-PDA analysis quantified syringic acid, 3-OH benzoic acid, t-ferullic acid, naringin, and epicatechin in a significant amount. All of the studied extracts/fractions displayed significant antioxidant capability, with methanol extract exhibiting the highest radical-scavenging activity, as measured by an inhibitory percentage of 81.4 ± 0.7 and an IC50 value of 1.3 ± 0.3. For enzyme inhibition experiments, the n-hexane fraction was shown to be highly potent against xanthine oxidase and urease enzymes, with respective IC50 values of 2.3 ± 0.5 and 1.1 ± 0.4 mg/mL. Similarly, the methanol extract demonstrated the strongest activity against the carbonic anhydrase enzyme, with an IC50 value of 2.2 ± 0.4 mg/mL. Moreover, all the studied extracts/fractions presented moderate antibacterial potential against seven bacterial strains. Molecular docking of the five molecules ß-amyrin, campesterol, ergosta-4,6,22-trien-3ß-ol, stigmasterol, and caryophyllene revealed the interaction of these ligands with the investigated enzyme (xanthine oxidase). The results of the present study suggested that the N. procumbens plant may be evaluated as a possible source of bioactive compounds with multifunctional therapeutic applications.

Dose Dependent Effects of Breynia cernua Against the Paraquat Induced Parkinsonism like Symptoms in Animals' Model: In Vitro, In Vivo and Mechanistic Studies.

The aims and objectives of the study were to evaluate the antiParkinson's (PD) potential of B cernua (BCE). B cernua (Poir.) Müll. Arg. (B cernua) is a member of the Phyllanthaceae family. HPLC revealed the presence of various phytochemicals. Study was conducted for 40 days. After PD induction by paraquat behavioural studies were carried out. Biochemical parameters such as DPPH, NO-scavenging, Ferrous reducing power, MDA, GSH, CAT, SOD, acetylcholinesterase (AChE), neurotransmitter estimation and TNF-α and IL-6 levels were determined. DPPH, NO-scavenging and Ferrous reducing power assays showed 78.02%, 48.05% and 71.45% inhibitions, respectively. There was significant improvement in motor functions and coordination in a dose-dependent manner (50 < 250 < 500 mg/kg) in PD rat model. Biochemical markers; SOD, CAT, GPx and GSH showed significant restoration (P < .001) while MDA showed significant decrease (P < .05). The AChE level was significantly reduced (P < .05) at 500 mg/kg while neurotransmitters were significantly improved (P < .001) in a dose-dependent fashion. The ELISA results showed significant (P < .001) down-regulation of IL-6 and TNF-α level. In conclusion, it is suggested that BCE has the potential to reduce the symptoms of PD.