Unveiling the antibacterial efficacy of thiazolo [3,2-a] pyrimidine: Synthesis, molecular docking, and molecular dynamic simulation.

Two series of C-Mannich base derivatives were synthesized and evaluated through the reaction of formaldehyde, two thiazolo-pyrimidine compounds, and various 2°-amines. The chemical structures and inherent properties of the synthesized compounds were authenticated using a variety of spectroscopic techniques. The aseptic bactericidal potential of the compounds was assessed alongside five common bacterial microbes, with Ampicillin employed as the reference drug. Compounds 9b and 9d demonstrated comparable antibacterial activity to ampicillin against Bacillus subtilis and Bacillus megaterium, respectively, at 100 µg/mL. Furthermore, compounds 9f and 10f exhibited noteworthy action against Staphylococcus aureus (MIC: 250 µg/mL). Compounds 10b and 10f displayed excellent efficacy versus Escherichia coli, boasting (MIC: 50 µg/mL). Molecular docking studies elucidated the necessary connections and energies of molecular entities with the E. coli DNA gyrase B enzyme, a pivotal target in bacterial DNA replication. Further thermodynamic stability of the ligand-receptor complex of 10b and 10f were further validated though 200 ns molecular dynamics simulation. The findings highlight the potential of these synthesized derivatives as effective antibacterial agents and provide valuable insights into their mechanism of action.

Quercetin increases the antidepressant-like effects of sclareol and antagonizes diazepam in thiopental sodium-induced sleeping mice: A possible GABAergic transmission intervention.

Quercetin is the most common polyphenolic flavonoid present in fruits and vegetables demonstrating versatile health-promoting effects. This study aimed to examine the effects of quercetin (QR) and sclareol (SCL) on the thiopental sodium (TS)-induced sleeping and forced swimming test (FST) mouse models. SCL (1, 5, and 10 mg/kg, p.o.) or QR (50 mg/kg, p.o.) and/or diazepam (DZP) (3 mg/kg, i.p.) were employed. After 30 min of TS induction, individual or combined effects on the animals were checked. In the FST test, the animals were subjected to forced swimming after 30 min of administration of the test and/or controls for 5 min. In this case, immobility time was measured. In silico studies were conducted to evaluate the involvement of GABA receptors. SCL (5 and 10 mg/kg) significantly increased the latency and decreased sleeping time compared to the control in the TS-induced sleeping time study. DZP (3 mg/kg) showed a sedative-like effect in animals in both sleeping and FST studies. QR (50 mg/kg) exhibited a similar pattern of activity as SCL. However, its effects were more prominent than those of SCL groups. SCL (10 mg/kg) altered the DZP-3-mediated effects. SCL-10 co-treated with QR-50 significantly (p < 0.05) increased the latency and decreased sleep time and immobility time, suggesting possible synergistic antidepressant-like effects. In silico studies revealed that SCL and QR demonstrated better binding affinities with GABAA receptor, especially α2, α3, and α5 subunits. Both compounds also exhibited good ADMET and drug-like properties. In animal studies, the both compounds worked synergistically to provide antidepressant-like effects in a slightly different fashion. As a conclusion, the combined administration of SCL and QR may be used in upcoming neurological clinical trials, according to in vivo and in silico findings. However, additional investigation is necessary to verify this behavior and clarify the potential mechanism of action.

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.

Daidzin enhances memory and the antischizophrenia drug olanzapine's effects, possibly through the 5-HT2A and D2 receptor interaction pathways.

Schizophrenia affects identification and disturbs our thinking and motivational capacity. Long-term use of daidzin (DZN) is evident to enhance attention and memory in experimental animals. This study aimed to investigate the effect of DZN on Swiss mice. To check animals' attention, identification, thinking, and motivational ability, we performed behavioral studies using marble burying, dust removal, and trained swimming protocols. For this, a total of 36 male Swiss albino mice were randomly divided into six groups, consisting of 6 animals in each group, as follows: control (vehicle), DZN-1.25, DZN-2.5, DZN-5 mg/kg, olanzapine (OLN)-2, and a combination of DZN-1.25 with OLN-2. Additionally, in silico studies are also performed to understand the possible molecular mechanisms behind this neurological effect. Findings suggest that DZN dose-dependently and significantly (p < .05) increased marble burying and removed dust while reducing the time to reach the target point. DZN-1.25 was found to enhance OLN's effect significantly (p < .05), possibly via agonizing its activity in animals. In silico findings suggest that DZN has strong binding affinities of -10.1 and -10.4 kcal/mol against human serotonin 2 A (5-HT2A) and dopamine 2 (D2) receptors, respectively. Additionally, DZN exhibits favorable pharmacokinetic and toxicity properties. We suppose that DZN may exert its attention- and memory-enhancing abilities by interacting with 5-HT2A and D2 receptors. It may exert a synergistic antischizophrenia-like effect with the standard drug, OLN. Further studies are required to discover the exact molecular mechanism for this neurological function in animals.

Assessment of sedative activity of fraxin: In vivo approach along with receptor binding affinity and molecular interaction with GABAergic system.

Insomnia is a sleep disorder in which you have trouble falling and/or staying asleep. This research aims to evaluate the sedative effects of fraxin (FX) on sleeping mice induced by thiopental sodium (TS). In addition, a molecular docking study was conducted to investigate the molecular processes underlying these effects. The study used adult male Swiss albino mice and administered FX (10 and 20 mg/kg, i.p.) and diazepam (DZP) (2 mg/kg) either separately or in combination within the different groups to examine their modulatory effects. After a period of 30 min, the mice that had been treated were administered (TS: 20 mg/kg, i.p.) to induce sleep. The onset of sleep for the mice and the length of their sleep were manually recorded. Additionally, a computational analysis was conducted to predict the role of gamma-aminobutyric acid (GABA) receptors in the sleep process and evaluate their pharmacokinetics and toxicity. The outcomes indicated that FX extended the length of sleep and reduced the time it took to fall asleep. When the combined treatment of FX and DZP showed synergistic sedative action. Also, FX had a binding affinity of -7.2 kcal/mol, while DZP showed -8.4 kcal/mol. The pharmacokinetic investigation of FX demonstrated favorable drug-likeness and strong pharmacokinetic characteristics. Ultimately, FX demonstrated a strong sedative impact in the mouse model, likely via interacting with the GABAA receptor pathways.

Screening of Multitarget Compounds against Acetaminophen Hepatic Toxicity Using In Silico, In Vitro, and In Vivo Approaches.

Combination therapy and multitarget drugs have recently attracted much attention as promising tools to fight against many challenging diseases and, thus, represent a new research focus area. The aim of the current project was to screen multitarget compounds and to study their individual and combined effects on acetaminophen-induced liver injury. In this study, 2 of the best hepatoprotective multitargeting compounds were selected from a pool of 40 major compounds present in Curcuma longa and Cinnamomum zeylanicum by using molecular docking, ADMET profiling, and Pfizer's rule of five. The two selected compounds, quercetin and curcumin, showed a high binding affinity for the CYP2E1 enzyme, MAPK, and TLR4 receptors that contribute to liver injury. The candidates caused the decreased viability of cancer cell lines (HepG2 and Huh7) but showed no effect on a normal cell line (Vero). Examination of biochemical parameters (ALT, AST, ALP, and bilirubin) showed the hepatoprotective effect of the candidate drugs in comparison with the control group, which was confirmed by histological findings. Taken together, quercetin and curcumin not only satisfied the drug-like assessment criterion and proved to be multitargeting by preventing liver damage but also showed anticancer activities.

Advancing Bioanalytical Method Validation: A Comprehensive ICH M10 Approach for Validating LC-MS/MS to Quantify Fluoxetine in Human Plasma and Its Application in Pharmacokinetic Studies.

A fast and sample cleanup approach for fluoxetine in human plasma was developed using protein precipitation coupled with LC-MS-MS. Samples were treated with methanol prior to LC-MS-MS analysis. Chromatographic separation was performed on a reverse phase column with an isocratic mobile phase of methanol and 10 mM ammonium formate pH acidified with formic acid (80:20, v/v) at a flow rate of 0.2 mL/min. The run time was 4 min. Mass parameters were optimized to monitor transitions at m/z [M + H]+ 310 > > 148 for fluoxetine and m/z [M + H]+ 315.1 > > 153 for fluoxetine-d5 as an internal standard. The lower limit of quantification and the dynamic range were 0.25 and 0.25-50 ng/mL, respectively. Linearity was good for intra-day and inter-day validations (R2 = 0.999). The matrix effect was acceptable with CV% < 15 and accuracy% < 15. The hemolytic effect was negligible. Fluoxetine was stable in human plasma for 48 h at room temperature (25 °C), for 12 months frozen at -25 °C, for 48 h in an auto-sampler at 6 °C, and for three freeze/thaw cycles. The validated method was applied in a pharmacokinetic study to determine the concentration of fluoxetine in plasma samples. The study provides a fast and simple bioanalytical method for routine analysis and may be particularly useful for bioequivalence studies. The method was successfully applied to a pharmacokinetic study of fixed-dose fluoxetine in nine healthy volunteers.

Synthesis, Anticancer Evaluation and in Silico Studies of 1,4-Dihydropyridines.

An efficient 1,4-dihydropyridine synthesis under mild conditions has been developed. Numerous substrates were tested, with yields of 1,4-dihydropridines ranging from good to excellent and a wide range of functional group tolerance. A549, HT-29, and HepG2 cancer cells were used to investigate the anticancer efficacy of each of the produced compounds. Additionally, in-silico docking studies were conducted to understand the structure-based features of the anticancer mechanism with the cancer medication target of Adenosine A2A receptor as well as the molecular level interactions of the compounds.

Assessing the In Vitro and In Vivo Performance of L-Carnitine-Loaded Nanoparticles in Combating Obesity.

Addressing obesity is a critical health concern of the century, necessitating urgent attention. L-carnitine (LC), an essential water-soluble compound, plays a pivotal role in lipid breakdown via ß-oxidation and facilitates the transport of long-chain fatty acids across mitochondrial membranes. However, LC's high hydrophilicity poses challenges to its diffusion through bilayers, resulting in limited bioavailability, a short half-life, and a lack of storage within the body, mandating frequent dosing. In our research, we developed LC-loaded nanoparticle lipid carriers (LC-NLCs) using economically viable and tissue-localized nanostructured lipid carriers (NLCs) to address these limitations. Employing the central composite design model, we optimized the formulation, employing the high-pressure homogenization (HPH) method and incorporating Poloxamer® 407 (surfactant), Compritol® 888 ATO (solid lipid), and oleic acid (liquid oil). A comprehensive assessment of nanoparticle physical attributes was performed, and an open-field test (OFT) was conducted on rats. We employed immunofluorescence assays targeting CRP and PPAR-γ, along with an in vivo rat study utilizing an isolated fat cell line to assess adipogenesis. The optimal formulation, with an average size of 76.4 ± 3.4 nm, was selected due to its significant efficacy in activating the PPAR-γ pathway. Our findings from the OFT revealed noteworthy impacts of LC-NLC formulations (0.1 mg/mL and 0.2 mg/mL) on adipocyte cells, surpassing regular L-carnitine formulations' effects (0.1 mg/mL and 0.2 mg/mL) by 169.26% and 156.63%, respectively (p < 0.05).

Targeting Transcriptional CDKs 7, 8, and 9 with Anilinopyrimidine Derivatives as Anticancer Agents: Design, Synthesis, Biological Evaluation and In Silico Studies.

Cyclin-dependent kinases (CDKs) are promising targets in chemotherapy. In this study, we report a series of 2-anilinopyrimidine derivatives with CDK inhibitory activity. Twenty-one compounds were synthesized and their CDK inhibitory and cytotoxic activities were evaluated. The representative compounds demonstrate potent antiproliferative activities toward different solid cancer cell lines and provide a promising strategy for the treatment of malignant tumors. Compound 5f was the most potent CDK7 inhibitor (IC50 = 0.479 µM), compound 5d was the most potent CDK8 inhibitor (IC50 = 0.716 µM), and compound 5b was the most potent CDK9 inhibitor (IC50 = 0.059 µM). All the compounds satisfied the Lipinski's rule of five (molecular weight < 500 Da, number of hydrogen bond acceptors <10, and octanol-water partition coefficient and hydrogen bond donor values below 5). Compound 5j is a good candidate for lead optimization because it has a non-hydrogen atom (N) of 23, an acceptable ligand efficiency value of 0.38673, and an acceptable ligand lipophilic efficiency value of 5.5526. The synthesized anilinopyrimidine derivatives have potential as anticancer agents.

New Indazol-Pyrimidine-Based Derivatives as Selective Anticancer Agents: Design, Synthesis, and In Silico Studies.

In this research study, the authors successfully synthesized potent new anticancer agents derived from indazol-pyrimidine. All the prepared compounds were tested for in vitro cell line inhibitory activity against three different cancerous cell lines. Results demonstrated that five of the novel compounds-4f, 4i, 4a, 4g, and 4d-possessed significant cytotoxic inhibitory activity against the MCF-7 cell line, with IC50 values of 1.629, 1.841, 2.958, 4.680, and 4.798 µM, respectively, compared to the reference drug with an IC50 value of 8.029 µM, thus demonstrating promising suppression power. Compounds 4i, 4g, 4e, 4d, and 4a showed effective cytotoxic activity stronger than the standard against Caco2 cells. Moreover, compounds 4a and 4i exhibited potent antiproliferative activity against the A549 cell line that was stronger than the reference drug. The most active products, 4f and 4i, werr e further examined for their mechanism of action. It turns out that they were capable of activating caspase-3/7 and, therefore, inducing apoptosis. However, produced a higher safety profile than the reference drug, towards the normal cells (MCF10a). Furthermore, the dynamic nature, binding interaction, and protein-ligand stability were explored through a Molecular Dynamics (MD) simulation study. Various analysis parameters (RMSD, RMSF, RoG, and SASA) from the MD simulation trajectory have suggested the stability of the compounds during the 20 ns MD simulation study. In silico ADMET results revealed that the synthesized compounds had low toxicity, good solubility, and an absorption profile since they met Lipinski's rule of five and Veber's rule. The present research highlights the potential of derivatives with indazole scaffolds bearing pyrimidine as a lead compound for designing anticancer agents.

Assessment of Health-Related Quality of Life in Chronic Kidney Disease Patients: A Hospital-Based Cross-Sectional Study.

Background: Health-related quality of life is rapidly becoming recognized as an important indicator of how a disease affects patient lives and for evaluating the quality of care, especially for chronic conditions such as chronic kidney disease (CKD). Objectives: This study is an attempt to assess the quality of life in patients with chronic kidney disease at MMIMSR and also identify characteristics that may be associated with their worsening quality of life. Materials and Methods: This cross-sectional investigation was conducted at the in-patient department (IPD) of the MMIMSR hospital. This study included 105 CKD patients and used a systematic random sampling method for quantitative analysis. This study utilized a 36-item short-form SF-36 (v1.3) questionnaire to assess HRQoL in CKD patients. Descriptive statistics were employed at the baseline. Chi square and ANOVA were used to draw comparisons between two groups or more than two groups, respectively. Logistic regression analysis was utilized to identify the potential QoL determinants. A p value of 0.05 or lower was used to determine statistical significance. Results: Among a total of 105 participants, the mean (±standard deviation) age was found to be 54.53 ± 13.47 years; 48 were male patients, and 57 were female patients. Diabetes Mellitus (61.9%), hypertension (56.2%), chronic glomerulonephritis (7.6%), chronic pyelonephritis (6.7%), and polycystic kidney disease (5.7%) were identified to be the most frequent disorders associated with CKD. The current study also demonstrated that the HRQoL score domains such as symptom problem list, the effect of kidney disease, and the burden of kidney disease decline significantly and progressively as the patient advances into higher stages of CKD (p = 0.005). A similar pattern was observed in work status, sleep, and general health (p < 0.005). Additionally, a statistically significant difference was noted for cognitive function, quality of social interaction, overall health, dialysis staff encouragement, patient satisfaction, social support, physical functioning, role of physical health, pain, emotional well-being, role of emotional health, social functioning, and energy fatigue (p < 0.005). The mean difference for PCS and MCS based on CKD stages was found to be statistically significant (p < 0.005). The PCS and MCS showed a positive correlation with GFR (r = 0.521), and Hb (r = 0.378), GFR (r = 0.836), and Hb (r = 0.488), respectively. Conclusions: The findings of this study demonstrated that a significant decrease in HRQoL was observed among CKD patients, with a progressive deterioration of HRQoL dimensions as the patient advances to end-stage renal disease. This study also revealed that CKD imposes various restrictions on patients' day-to-day lives, particularly in terms of their physical and mental functioning, even in the initial stages of the disease.

Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors.

Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcriptional elongation, through which short-lived antiapoptotic proteins are overexpressed and make cancer cells resistant to apoptosis. Therefore, CDK9 inhibition depletes antiapoptotic proteins, which in turn leads to the reinstatement of apoptosis in cancer cells. Twenty-seven compounds were synthesized, and their CDK9 inhibitory and cytotoxic activities were evaluated. Compounds 7, 9, and 25 were the most potent CDK9 inhibitors, with IC50 values of 0.115, 0.131, and 0.142 µM, respectively. The binding modes of these molecules were studied via molecular docking, which shows that they occupy the adenosine triphosphate binding site of CDK9. Of these three molecules, compound 25 shows good drug-like properties, as it does not violate Lipinski's rule of five. In addition, this molecule shows promising ligand and lipophilic efficiency values and is an ideal candidate for further optimization.

Preparation and characterization of Meta-bromo-thiolactone calcium alginate nanoparticles.

Recently, the focus has been shifting toward Quorum sensing inhibitors which reduce Pseudomonas aeruginosa virulence factors, alleviating infections. In this work, me-ta-bromo-thiolactone (mBTL), a potent quorum and virulence inhibitor for the Pseudomonas aeruginosa strains, were formulated in calcium alginate nanoparticles (CANPs). Alginate is used as nutrients and as backbone virulence aspect for Pseudomonas and therefore was chosen. mBTL-loaded-CANPs were characterized for particle size, polydispersity index, zeta potential, morphology visualized by Transmission Electron Microscopy (TEM) and drug release profile. Chemical and physical analysis of formulated mBTL-loaded-CANPs were evaluated using Fourier transform infrared Spectroscopy (FTIR) and differential scanning calorimetry (DSC) and Physical stability of mBTL-loaded-CANPs assessed at various temperature 25 ± 1 °C, 4 ± 0.5 °C and -30° ± 1 °C over a period of 4 and 9 months. Synthesized CANPs showed nano-size particles ranging from 140 to 200 nm with spherical particles for plain CANPS and irregular shape for mBTL-loaded-CANPs with a sustainable release profile over 48hrs. FTIR showed stable structure of loaded-mBTL and DSC displayed no interaction between mBTL and polymer. State of released mBTL from CANPs kept at 25 °C, 4 °C and -30 °C over 4 and 9 months showed stable formula at room temperature which kept as a goal of nanoparticles storage. The findings of this study revealed successful preparation of mBTL-loaded-CANPs.

Synthesis, biological evaluations and computational studies of N-(3-(-2-(7-Chloroquinolin-2-yl)vinyl) benzylidene)anilines as fungal biofilm inhibitors.

In the present investigation, new chloroquinoline derivatives bearing vinyl benzylidene aniline substituents at 2nd position were synthesized and screed for biofilm inhibitory, antifungal and antibacterial activity. The result of biofilm inhibition of C. albicans suggested that compounds 5j (IC50 value = 51.2 µM) and 5a (IC50 value = 66.2 µM) possess promising antibiofilm inhibition when compared with the standard antifungal drug fluconazole (IC50 = 40.0 µM). Two compounds 5a (MIC = 94.2 µg/mL) and 5f (MIC = 98.8 µg/mL) also exhibited good antifungal activity comparable to standard drug fluconazole (MIC = 50.0 µg/mL). The antibacterial screening against four strains of bacteria viz. E. coli, P. aeruginosa, B. subtilis, and S. aureus suggested their potential antibacterial activity and especially all the compounds except 5g were found more active than the standard drug ciprofloxacin against B. subtilis. To further gain insights into the possible mechanism of these compounds in biofilm inhibition through the agglutinin like protein (Als), molecular docking and molecular dynamics simulation studies were carried out. Molecular modeling studies suggested the clear role in inhibition of this protein and the resulting biofilm inhibitory activity.

Computational Study of Natural Compounds for the Clearance of Amyloid-Βeta: A Potential Therapeutic Management Strategy for Alzheimer's Disease.

Alzheimer's disease (AD) is a widespread dynamic neurodegenerative malady. Its etiology is still not clear. One of the foremost pathological features is the extracellular deposits of Amyloid-beta (Aß) peptides in senile plaques. The interaction of Aß and the receptor for advanced glycation end products at the blood-brain barrier is also observed in AD, which not only causes the neurovascular anxiety and articulation of proinflammatory cytokines, but also directs reduction of cerebral bloodstream by upgrading the emission of endothelin-1 to induce vasoconstriction. In this process, RAGE is deemed responsible for the influx of Aß into the brain through BBB. In the current study, we predicted the interaction potential of the natural compounds vincamine, ajmalicine and emetine with the Aß peptide concerned in the treatment of AD against the standard control, curcumin, to validate the Aß peptide-compounds results. Protein-protein interaction studies have also been carried out to see their potential to inhibit the binding process of Aß and RAGE. Moreover, the current study verifies that ligands are more capable inhibitors of a selected target compared to positive control with reference to ΔG values. The inhibition of Aß and its interaction with RAGE may be valuable in proposing the next round of lead compounds for effective Alzheimer's disease treatment.

Quercetin and Kaempferol as Multi-Targeting Antidiabetic Agents against Mouse Model of Chemically Induced Type 2 Diabetes.

Diabetes, a multifactorial metabolic disorder, demands the discovery of multi-targeting drugs with minimal side effects. This study investigated the multi-targeting antidiabetic potential of quercetin and kaempferol. The druggability and binding affinities of both compounds towards multiple antidiabetic targets were explored using pharmacokinetic and docking software (AutoDock Vina 1.1.2). Our findings showed that quercetin and kaempferol obey Lipinski's rule of five and exhibit desirable ADMET (absorption, distribution, metabolism excretion, and toxicity) profiles. Both compounds showed higher binding affinities towards C-reactive protein (CRP), interleukin-1 (IL-1), dipeptidyl peptidase-4 (DPP-IV), peroxisome proliferator-activated receptor gamma (PPARG), protein tyrosine phosphatase (PTP), and sodium-glucose co-transporter-1 (SGLT-1) compared to metformin (the positive control). Both quercetin and kaempferol inhibited α-amylase activity (in vitro) up to 20.30 ± 0.49 and 37.43 ± 0.42%, respectively. Their oral supplementation significantly reduced blood glucose levels (p < 0.001), improved lipid profile (p < 0.001), and enhanced total antioxidant status (p < 0.01) in streptozotocin-nicotinamide (STZ-NA)-induced diabetic mice. Additionally, both compounds significantly inhibited the proliferation of Huh-7 and HepG2 (cancer cells) (p < 0.0001) with no effect on the viability of Vero cell line (non-cancer). In conclusion, quercetin and kaempferol demonstrated higher binding affinities towards multiple targets than metformin. In vitro and in vivo antidiabetic potential along with the anticancer activities of both compounds suggest promise for further development in diabetes management. The combination of both drugs did not show a synergistic effect, possibly due to their same target on the receptors.

Sedative Effects of Daidzin, Possibly Through the GABAA Receptor Interaction Pathway: In Vivo Approach with Molecular Dynamic Simulations.

The soy isoflavone daidzin (DZN) has been considered a hopeful bioactive compound having diverse biological activities, including anxiolytic, memory-enhancing, and antiepileptic effects, in experimental animals. However, its sedative and hypnotic effects are yet to be discovered. This study aimed to evaluate its sedative/hypnotic effect on Swiss mice. Additionally, in silico studies were also performed to see the possible molecular mechanisms behind the tested neurological effect. For this, male Swiss albino mice were treated with DZN (5, 10, or 20 mg/kg) intraperitoneally (i.p.) with or without the standard GABAergic medication diazepam (DZP) and/or flumazenil (FLU) and checked for the onset and duration of sleeping time using thiopental sodium-induced as well as DZP-induced sleeping tests. A molecular docking study was also performed to check its interaction capacity with the α1 and ß2 subunits of the GABAA receptor. Findings suggest that DZN dose-dependently and significantly reduced the latency while increasing the duration of sleep in animals. In combination therapy, DZN shows synergistic effects with the DZP-2 and DZP-2 + FLU-0.01 groups, resulting in significantly (p < 0.05) reduced latency and increased sleep duration. Further, molecular docking studies demonstrate that DZN has a strong binding affinity of - 7.2 kcal/mol, which is closer to the standard ligand DZP (- 8.3 kcal/mol) against the GABAA (6X3X) receptor. Molecular dynamic simulations indicated stability and similar binding locations for DZP and DZN with 6X3X. In conclusion, DZN shows sedative effects on Swiss mice, possibly through the GABAA receptor interaction pathway.

Piperine's potential in treating polycystic ovarian syndrome explored through in-silico docking.

Polycystic Ovarian Syndrome (PCOS) is a multifaceted metabolic and hormonal condition that impacts women in their procreative ages, identified by ovarian dysfunction, hyperandrogenaemia overweight and insulin insensitivity. The piperine, an important alkaloid compound of black pepper has shown promise in modulating various physiological processes. In this work, employed computational docking studies to explore the potential of piperine as a treatment for PCOS. Utilizing computational methods, we analyzed the binding interactions between piperine and key molecular targets implicated in PCOS pathogenesis, including hyperandrogenism, and "oligomenorrhea. The network pharmacology analysis report found 988 PCOS-related genes, 108 hyperandrogenism-related genes, and 377 oligomenorrhea-related genes, and we finally shortlisted 5 common genes in PCOS, hyperandrogenism, and "oligomenorrhea": NR3C1, PPARG, FOS, CYP17A1, and H6PD. Our results reveal favorable binding affinities with PPARG (-8.34 Kcal/mol) and H6PD (-8.70 Kcal/mol) and interaction patterns, suggesting the potential of piperine to modulate these targets. Moreover, the reliability of the piperine-target interactions was revealed by molecular simulations studies. These findings support further experimental investigations to validate the therapeutic efficacy of piperine in PCOS management. The integration of computational approaches with experimental studies has the potential to lay the groundwork for the creation of new therapies specifically targeting PCOS and related endocrine disorders.

Phytol exerts sedative-like effects and modulates the diazepam and flumazenil's action, possibly through the GABAA receptor interaction pathway.

This study aimed at the evaluation of the sedative effect of phytol (PHY) with possible molecular mechanisms through in vivo and in silico studies. For this, adult male mice were randomly divided into six individual groups, namely control (vehicle), two standards (DZP: diazepam at 2 m/kg, FLU: flumazenil at 0.1 mg/kg), three test groups (PHY at 25, 50, and 75 mg/kg), and three combined groups with the DZP-2 and/or FLU-0.1 with PHY-75 mg/kg. After thirty minutes, each animal was treated with thiopental sodium (TS) at 40 mg/kg to produce sedation and observed for latency and duration of sleep up to 4 h. In silico studies were performed with the 6X3X protein of the GABAA receptor α1 and ß2 subunits. The results demonstrate that PHY dose-dependently enhanced sleep duration in animals. However, it produced an insignificant sleep duration compared to the control and standard groups. It also significantly (p < 0.05) decreased the latency and increased the duration of sleep with DZP-2, while reducing these parameters with FLU-0.1. In in silico studies, DZP and FLU exhibited binding affinities with 6X3X by -6.8 and -6.9 kcal/mol, respectively, while PHY exhibited -6.9 kcal/mol. Taken together, PHY may exert a sedative-like effect in TS-induced sleeping mice and modulate the effects of DZP and FLU, possibly through interacting with the 6X3X protein of the GABAA receptor. PHY may be one of the good candidates for the management of sleep disturbances, such as insomnia.