Exploring the Potential Biological Activities of Pyrazole-Based Schiff Bases as Anti-Diabetic, Anti-Alzheimer's, Anti-Inflammatory, and Cytotoxic Agents: In Vitro Studies with Computational Predictions.

In this innovative research, we aim to reveal pyrazole-based Schiff bases as new multi-target agents. In this context, we re-synthesized three sets of pyrazole-based Schiff bases, 5a-f, 6a-f, and 7a-f, to evaluate their biological applications. The data from in vitro biological assays (including antioxidant and scavenging activities, anti-diabetes, anti-Alzheimer's, and anti-inflammatory properties) of the pyrazole-based Schiff bases 5a-f, 6a-f, and 7a-f showed that the six pyrazole-based Schiff bases 5a, 5d, 5e, 5f, 7a, and 7f possess the highest biological properties among the compounds evaluated. The cytotoxicity against lung (A549) and colon (Caco-2) human cancer types, as well as normal lung (WI-38) cell lines, was evaluated. The data from the cytotoxicity investigation demonstrated that the three Schiff bases 5d, 5e, and 7a are active against lung (A549) cells, while the two Schiff bases 5e and 7a exhibited the highest cytotoxicity towards colon (Caco-2) cells. Additionally, the enzymatic activities against caspase-3 and Bcl-2 of the six pyrazole-based Schiff bases 5a, 5d, 5e, 5f, 7a, and 7f were evaluated. Furthermore, we assessed the in silico absorption, distribution, metabolism, and toxicity (ADMT) properties of the more potent pyrazole-based Schiff bases. After modifying the structures of the six pyrazole-based Schiff bases, we plan to further extend the studies in the future.

Synthesis, in silico ADMET prediction analysis, and pharmacological evaluation of sulfonamide derivatives tethered with pyrazole or pyridine as anti-diabetic and anti-Alzheimer's agents.

Based on previous developments of our research programs in trying to find new compounds with multiple biological targets such as antioxidant, anti-diabetic, anti-Alzheimer's, and anti-arthritic agents. In the context, a novel series of sulfonamide derivatives based on the pyrazole or pyridine moieties 3a, b, 7-9, 11-13, 15a, b, and 16 were synthesized from amine compounds with sulfonyl chloride derivatives. The structures of sulfonamide derivatives were elucidated via spectroscopy (1H and 13C NMR). The sulfonamide derivatives were biologically assessed in vitro for their anti-diabetic (α-amylase and α-glucosidase inhibition) and anti-Alzheimer's (acetylcholinesterase inhibition) activities. The biological results revealed that compound 15a is a powerful enzyme inhibitor for α-amylase and α-glucosidase. Also, compound 15b demonstrated inhibitor activity against the acetylcholinesterase enzyme. The structure-activity relationship study of sulfonamide derivatives was accomplished. Furthermore, complementary in silico molecular properties, drug-likeness, ADMET prediction, and surface properties of the two more powerful derivatives 15a and 15b were fulfilled and computed. These studies recommend 15a and 15b as candidates with modifications in their structures before the in vivo assays.

In vitro biological studies and computational prediction-based analyses of pyrazolo[1,5-a]pyrimidine derivatives.

There is a need for new pharmaceutical discoveries from bioactive nitrogenous derivatives due to the emergence of scourges, numerous pandemics, and diverse health problems. In this context, pyrazolo[1,5-a]pyrimidine derivatives 12a and 12b were synthesized and screened to evaluate their biological potentials in vitro as antioxidants, anti-diabetics, anti-Alzheimer's, anti-arthritics, and anti-cancer agents. Additionally, the computational pharmacokinetic and toxicity properties of the two pyrazolo[1,5-a]pyrimidines 12a and 12b were calculated and analyzed. The preliminary studies and results of this work represent the initial steps toward more advanced studies and define the bioactive chemical structure of pyrazolo[1,5-a]pyrimidine derivatives with the goal of exploring new drugs to address numerous health problems.

Using Selenium-enriched Mutated Probiotics as Enhancer for Fertility Parameters in Mice.

Increasing fertility rates have become one of the factors that concern all people in the world. Therefore, the study aims to use two mutated strains of probiotics enriched with selenium (PSe40/60/1 and BSe50/20/1) to improve fertility. Thirty Swiss albino male mice were divided into three groups; control, LP + S was given Lactobacillus plantarum PSe40/60/1 plus selenium, and BL + S was given Bifidobacterium longum BSe50/20/1 plus selenium. Free testosterone, LH, and FSH were measured in serum by biochemical analysis. Testicular tissues were examined by histopathological analysis. The count and motility of sperm, and sperm abnormalities were determined by microscopic examination. The method of qRT-PCR was used to detect gene expression of Tspyl1, Hsd3b6, and Star genes. The biochemical results showed that serum content of free testosterone (FT) hormone had significantly increase in the BL + S and LP + S groups compared with control. Levels of LH and FSH hormones were the highest in the BL + S group. The treated groups showed all developmental stages of spermatogenesis, including spermatogenesis, spermatocytes, and seminiferous tubule spermatids, as well as intact Sertoli cells and Leydig cells without changes. When compared to the control group, sperm count and motility increased in the BL + S group, while sperm abnormalities decreased. The expression of Tspyl1 gene in testicular tissues decreased in the LP + S and BL + S groups, while the expression of Star and Hsd3b6 genes was higher in the BL + S group and lower in the LP + S group compared with the control group. Therefore, Bifidobacterium longum BSe50/20/1 enriched with selenium could be useful in enhancing male fertility.

Potentiometric planar platforms modified with a multiwalled carbon nanotube/polyaniline nanocomposite and based on imprinted polymers for erythromycin assessment.

A screen-printed potentiometric sensor for the erythromycin macrolide antibiotic (ERY) that is affordable, highly selective, and sensitive is made, described, and used for drug monitoring. Two circular carbon dots with a diameter of 4 mm make up the sensor. Multiwalled carbon nanotubes and polyaniline (f-MWCNTs/PANi) nanocomposites are used to change one carbon spot, which is then used as an ion-to-electron transfer material. Ag/AgCl is applied to the other spot, which is then used as a reference electrode. A solid-state polyvinyl butyral (PVB) is placed onto the second carbon spot to work as a reference electrode, and an ERY molecularly imprinted drug polymer (MIP) is coated onto the f-MWCNTs/PANi-containing strip to serve as a drug identification sensing material. Chronopotentiometry (CP) is used to analyze the integrated sensor's performance characteristics. It is confirmed that f-MWCNTs/PANi has an increased impact on the potential stability as well as the sensing membrane's interfacial double-layer capacitance. At a detection limit of 9.6 ± 0.4 × 10-7 M, the developed sensor exhibits a Nernstian slope of 54.0 ± 0.5 mV per decade (R2 = 0.9994) over the linear range of 4.6 × 10-6 to 1.0 × 10-3 M. When exposed to different related substances such azithromycin, clarithromycin, dirithromycin, paracetamol, and ascorbic acid, the sensor exhibits excellent selectivity. For the direct potentiometric determination of ERY in some pharmaceutical formulations and in samples of spiked human urine, the assay method has been validated and shown to be adequate. The obtained recovery ranges from 93.0 ± 0.5 to 104.3 ± 0.7 of the nominal or spiked concentration, with a mean relative standard deviation of ±0.6%. Due to the near closeness of the responsive membrane and the liquid junction, the use of all-solid-state electrodes coupled with a planar disposable platform enables applications with a minimum sample volume. The effectiveness of the suggested sensor in a complex urine matrix points to its use in hospitals for quick overdose patient detection as well as for quality control/quality assurance tests in the pharmaceutical sector.

Paper-Based Analytical Device Based on Potentiometric Transduction for Sensitive Determination of Phenobarbital.

In medicine, barbiturates are a class of depressive medications used as hypnotics, anticonvulsants, and anxiolytics. For the treatment of specific forms of epilepsy and seizures in young children in underdeveloped countries, the World Health Organization recommends phenobarbital (PBAR), a barbiturate drug. This review describes the fabrication and characterization of a paper-based analytical apparatus for phenobarbital detection that is straightforward, affordable, portable, and disposable. All of the solid-state ion-selective electrodes (ISEs) for PBAR as well as a Ag/AgCl reference electrode were constructed and optimized on a nonconductive paper substrate. Using carbon nanotube ink, the sensors were made to function as an ion-to-electron transducer and to make the paper conductive. A suitable polymeric membrane is drop-cast onto the surface of the carbon ink orifice. The pyrido-tetrapeptide and pyrido-hexapeptide derivatives, which were recently synthesized, functioned as distinct ionophores in the PBAR-membrane sensor, enabling its detection. With a detection limit of 5.0 × 10-7 M, the manufactured analytical device demonstrated a Nernstian response to PBAR anions in 50 mM phosphate buffer, pH 8.5, over a linear range of 1.0 × 10-6 to 1.0 × 10-3 M. The PBAR-based sensors showed quick (less than 5 s) response times for PBAR ion detection. The modified separate solution method was utilized to evaluate the selectivity pattern of these novel ionophores with respect to PBAR ions in comparison to other common anions. The analytical instrument that was exhibited on paper had good precision both within and between days. The suggested technology assisted in the detection of trace amounts of PBAR in real pharmaceutical samples. A comparison was made between the data acquired using the HPLC reference method and the information obtained by the recommended potentiometric approach. The described paper-based analytical device may be a good choice for point-of-care PBAR determination because it is cheap and easy to find and can self-pump (especially when combined with potentiometric detection).

Nanoparticles of a Pyrazolo-Pyridazine Derivative as Potential EGFR and CDK-2 Inhibitors: Design, Structure Determination, Anticancer Evaluation and In Silico Studies.

The strategic planning of this study is based upon using the nanoformulation method to prepare nanoparticles 4-SLNs and 4-LPHNPs of the previously prepared 4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-3-amine (4) after confirming its structure with single crystal X-ray analysis. These nanoparticles exhibited promising cytotoxic activity against HepG-2, HCT-116 and MCF-7 cancer cell lines in comparison with the reference doxorubicin and the original derivative 4. Moreover, their inhibitory assessment against EGFR and CDK-2/cyclin A2 displayed improved and more favorable impact than the parent 4 and the references. Detection of their influence upon cancer biomarkers revealed upregulation of Bax, p53 and caspase-3 levels and downregulation of Bcl-2 levels. The docking simulation demonstrated that the presence of the pyrazolo[3,4-c]pyridazin-3-amine scaffold is amenable to enclosure and binding well within EGFR and CDK-2 receptors through different hydrophilic interactions. The pharmacokinetic and physicochemical properties of target 4 were also assessed with ADME investigation, and the outcome indicated good drug-like characteristics.

Investigations of Electronic, Structural, and In Silico Anticancer Potential of Persuasive Phytoestrogenic Isoflavene-Based Mannich Bases.

Isoflavenes have received the greatest research attention among the many groups of phytoestrogens. In this study, various isoflavene-based Mannich bases were selected for their theoretical studies. The purpose of this research was to discover the binding potential of all the designated Mannich bases acting as inhibitors against cancerous proteins EGFR, cMet, hTrkA, and HER2 (PDB codes: 5GTY, 3RHK, 6PL2, and 7JXH, respectively). For their virtual screening, DFT calculations and molecular docking studies were undertaken using in silico software. Docking studies predicted that ligands 5 and 15 exhibited the highest docking score by forming hydrogen bonds within the active pocket of protein 6PL2, ligands 1 and 15 both with protein 3RHK, and 7JXH, 12, and 17 with protein 5GTY. Rendering to the trends in polarizability and dipole moment, the energy gap values (0.2175 eV, 0.2106 eV) for the firm conformers of Mannich bases (1 and 4) replicate the increase in bioactivity and chemical reactivity. The energy gap values (0.2214 eV and 0.2172 eV) of benzoxazine-substituted isoflavene-based Mannich bases (9 and 10) reflect the increase in chemical potential due to the most stable conformational arrangements. The energy gap values (0.2188 eV and 0.2181 eV) of isoflavenes with tertiary amine-based Mannich bases (14 and 17) reflect the increase in chemical reactivity and bioactivity due to the most stable conformational arrangements. ADME was also employed to explore the pharmacokinetic properties of targeted moieties. This study revealed that these ligands have a strong potential to be used as drugs for cancer treatment.

Phytochemical Analysis, In Vitro Biological Activities, and Computer-Aided Analysis of Potentilla nepalensis Hook Compounds as Potential Melanoma Inhibitors Based on Molecular Docking, MD Simulations, and ADMET.

Potentilla nepalensis Hook is a perennial Himalayan medicinal herb of the Rosaceae family. The present study aimed to evaluate biological activities such as the antioxidant, antibacterial, and anticancer activities of roots and shoots of P. nepalensis and its synergistic antibacterial activity with antibacterial drugs. Folin-Ciocalteau and aluminium chloride methods were used for the calculation of total phenolic (TPC) and flavonoid content (TFC). A DPPH radical scavenging assay and broth dilution method were used for the determination of the antioxidant and antibacterial activity of the root and shoot extracts of P. nepalensis. Cytotoxic activity was determined using a colorimetric MTT assay. Further, phytochemical characterization of the root and shoot extracts was performed using the Gas chromatography-mass spectrophotometry (GC-MS) method. The TPC and TFC were found to be higher in the methanolic root extract of P. nepalensis. The methanolic shoot extract of P. nepalensis showed good antioxidant activity, while then-hexane root extract of P. nepalensis showed strong cytotoxic activity against tested SK-MEL-28 cells. Subsequently, in silico molecular docking studies of the identified bioactive compounds predicted potential anticancer properties. This study can lead to the production of new herbal medicines for various diseases employing P. nepalensis, leading to the creation of new medications.

Alleviative effects of pinostrobin against cadmium-induced renal toxicity in rats by reducing oxidative stress, apoptosis, inflammation, and mitochondrial dysfunction.

Introduction: Cadmium (Cd) is a highly toxic heavy metal that can be found everywhere in the environment and can have harmful effects on both human and animal health. Pinostrobin (PSB) is a bioactive natural flavonoid isolated from Boesenbergia rotunda with several pharmacological properties, such as antiinflammatory, anticancer, antioxidant, and antiviral. This investigation was intended to assess the therapeutic potential of PSB against Cd-induced kidney damage in rats. Methods: In total, 48 Sprague Dawley rats were divided into four groups: a control, a Cd (5 mg/kg), a Cd + PSB group (5 mg/kg Cd and 10 mg/kg PSB), and a PSB group (10 mg/kg) that received supplementation for 30 days. Results: Exposure to Cd led to a decrease in the activities of catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX), whereas levels of reactive oxygen species (ROS) and malondialdehyde (MDA) increased. Cd exposure also caused a substantial increase in urea, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and creatinine levels. Moreover, a noticeable decline was noticed in creatinine clearance. Moreover, Cd exposure considerably increased the levels of inflammatory indices, including interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), nuclear factor kappa-B (NF-kB), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) activity. Cd treatment decreased the expression of the antiapoptotic markers (Bcl-2) while increasing the expression of apoptotic markers (Bax and Caspase-3). Furthermore, Cd treatment substantially reduced the TCA cycle enzyme activity, such as alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, and isocitrate dehydrogenase. Moreover, mitochondrial electron transport chain enzymes, succinatedehydrogenase, NADH dehydrogenase, cytochrome c-oxidase, and coenzyme Q-cytochrome reductase activities were also decreased following Cd exposure. PSB administration substantially reduced the mitochondrial membrane potential while inducing significant histological damage. However, PSB treatment significantly reduced Cd-mediated renal damage in rats. Conclusion: Thus, the present investigation discovered that PSB has ameliorative potential against Cd-induced renal dysfunction in rats.

Anti-inflammatory activity of novel derivatives of pyrazolo [3,4d] pyridazine against digestive system inflammation.

The digestive system is exposed to severe inflammation as a result of taking some medications that have gastrointestinal side effects. Sixty Swiss-albino male mice were randomly distributed into six groups to treat inflammations of the colon, stomach, and small intestine caused by taking high doses of diclofenac (D), with two novel synthesized compounds, pyrazolo [3,4 d] pyridazine derivatives (Co1 and Co2). Myeloperoxidase enzyme activity was determined in the colon and small intestinal tissues. Serum contents of TNF-α, IL-22, IgG, and IgM were determined by ELISA. Histopathological examinations of the colon, small intestinal, and stomach tissues were microscopically analyzed. TNF-α, IL-22, and TNFSF11 gene expression were measured in the colon, intestinal, and spleen using qRT-PCR. Diclofenac caused surface columnar epithelial cell loss, focal necrosis of the gastric mucosa, inflammatory cell infiltration, and congested blood vessels in the stomach, colon, and small intestinal tissues. Co1 component was found to be better than Co2 component in reducing the focal necrosis of gastric mucosa and improving the histological structures of the stomach, colon, and small intestinal tissues. After 14 days, the activity of the myeloperoxidase enzyme was increased in group D and decreased in groups DCo1, DCo2, Co1, and Co2. Serum concentrations of TNF-α and IgG were increased, while IL-22 and IGM were reduced in the D, DCo1, and DCo2 groups compared with the Co1 and control groups. TNF-α gene was upregulated in the D group and downregulated in the Co1 group, while the IL-22 gene was downregulated in the D group and upregulated in the Co1 group compared with the control group. The CO1 component may be useful in reducing digestive system inflammation.

Acid protease functionalized novel silver nanoparticles (APTs-AgNPs): A new approach towards photocatalytic and biological applications.

Herein, we described for the first time, an efficient biogenic synthesis of APTs-AgNPs using acid protease from Melilotus indicus leaf extract. The acid protease (APTs) has an essential role in the stabilization, reduction, and capping of APTs-AgNPs. The crystalline nature, size, and surface morphology of APTs-AgNPs were examined using different techniques such as XRD, UV, FTIR, SEM, EDS, HRTEM, and DLS analysis. The generated APTs-AgNPs demonstrated notable performance as dual functionality (photocatalyst and antibacterial disinfection). By destroying 91 % of methylene blue (MB) in <90 min of exposure, APTs-AgNPs demonstrated remarkable photocatalytic activity. APTs-AgNPs also showed remarkable stability as a photocatalyst after five test cycles. Furthermore, the APTs-AgNPs was found to be a potent antibacterial agent with inhibition zones of 30(±0.5 mm), 27(±0.4 mm), 16(±0.1 mm), and 19(±0.7 mm) against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria, respectively, under both light and dark conditions. Furthermore, APTs-AgNPs effectively scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, demonstrating their potent antioxidant activity. The outcomes of this study thus demonstrates the dual functionality of APTs-AgNPs produced using the biogenic approach method as a photocatalyst and an antibacterial agent for effective microbial and environmental control.

Point-of-care paper-based analytical device for potentiometric detection of myoglobin as a cardiovascular disease biomarker.

One of the cardiac biomarkers, myoglobin (Mb), is important in the rapid identification of cardio-vascular disorders. Therefore, point-of-care monitoring is essential. Pursuing this goal, a robust, reliable, and affordable paper-based analytical apparatus for potentiometric sensing has been developed and characterized. The molecular imprint technique was used to create a customized biomimetic antibody for myoglobin (Mb) on the surface of carboxylated multiwalled carbon nanotubes (MWCNT-COOH). This was accomplished by attaching Mb to carboxylated MWCNTs' surfaces and then filling the empty spaces through the mild polymerization of acrylamide in N,N-methylenebisacrylamide and ammonium persulphate. The modification of the MWCNTs' surface was verified by SEM and FTIR analysis. A hydrophobic paper substrate coated with fluorinated alkyl silane (CF3(CF2)7CH2CH2SiCl3, CF10) has been coupled with a printed all-solid-state Ag/AgCl reference electrode. The presented sensors showed a linear range of 5.0 × 10-8 to 1.0 × 10-4 M with a potentiometric slope of -57.1 ± 0.3 mV decade-1 (R2 = 0.9998) and a detection limit of 28 nM at pH 4. Compared to creatinine, sucrose, fructose, galactose, sodium glutamate, thiamine, alanine, ammonium, uric acid, albumin, glutamine, guanine, troponine T, and glucose, the sensor showed good selectivity for Mb. It demonstrated a good recovery for the detection of Mb in several fake serum samples (93.0-103.3%), with an average relative standard deviation of 4.5%. The current approach might be viewed as a potentially fruitful analytical tool for obtaining disposable, cost-effective paper-based potentiometric sensing devices. These types of analytical devices can be potentially manufacturable at large scales in clinical analysis.

Exploring Antimicrobial Features for New Imidazo[4,5-b]pyridine Derivatives Based on Experimental and Theoretical Study.

5-bromopyridine-2,3-diamine reacted with benzaldehyde to afford the corresponding 6-Bromo-2-phenyl-3H-imidazo[4,5-b]pyridine (1). The reaction of the latter compound (1) with a series of halogenated derivatives under conditions of phase transfer catalysis solid-liquid (CTP) allows the isolation of the expected regioisomers compounds (2-8). The alkylation reaction of (1) gives, each time, two regioisomers, N3 and N4; in the case of ethyl bromoactate, the reaction gives, at the same time, the three N1, N3 and N4 regioisomers. The structures of synthesized compounds were elucidated on the basis of different spectral data (1H NMR, 13C NMR), X-Ray diffraction and theoretical study using the DFT method, and confirmed for each compound. Hirshfeld surface analysis was used to determine the intermolecular interactions responsible for the stabilization of the molecule. Density functional theory was used to optimize the compounds, and the HOMO-LUMO energy gap was calculated, which was used to examine the inter/intra molecular charge transfer. The molecular electrostatic potential map was calculated to investigate the reactive sites that were present in the molecule. In order to determine the potential mode of interactions with DHFR active sites, the three N1, N3 and N4 regioisomers were further subjected to molecular docking study. The results confirmed that these analogs adopted numerous important interactions, with the amino acid of the enzyme being targeted. Thus, the most docking efficient molecules, 2 and 4, were tested in vitro for their antibacterial activity against Gram-positive bacteria (Bacillus cereus) and Gram-negative bacteria (Escherichia coli). Gram-positive bacteria were more sensitive to the action of these compounds compared to the Gram-negative, which were much more resistant.

Isolation and Bioassay of a New Terminalone A from Terminalia arjuna.

Terminalia arjuna possesses significant cardioprotective, antidiabetic and antioxidant properties as these properties are described in Ayurveda. In the present study, three flavonoids were isolated through the separation and chromatographic purification of the whole plant material of T. arjuna. Spectroscopic characterization identified one of them as a new flavonoid "Terminalone A (1)" and two known flavonoids i.e., 6-hydroxy-2-(4-hydroxyphenyl)-7-methoxy-4H-chromen-4-one (2) and 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-chromen-4-one (3). The bioactivity studies showed considerable antibacterial and antioxidant (DPPH radical scavenging) potential for all the three compounds 1-3 where the compound 1 showed strong antibacterial and antioxidant activity.

Purification and thermodynamic characterization of acid protease with novel properties from Melilotus indicus leaves.

A thermostable acid protease from M. indicus leaves was purified 10-fold using a 4-step protocol. We were able to isolate a purified protease fraction with a molecular weight of 50 kDa and exhibited maximal protease activity at pH 4.0 and 40 °C. Structural analysis revealed that the protease is monomeric and non-glycosylated. The addition of epoxy monocarboxylic acid, iodoacetic acid, and dimethyl sulfoxide significantly reduced protease activity while dramatically increasing the inhibition of Mn2+, Fe2+, and Cu2+. The activation energy of the hydrolysis reaction (33.33 kJ mol-1) and activation energy (Ed = 105 kJ mol-1), the standard enthalpy variation of reversible protease unfolding (2.58 kJ/mol) were calculated after activity measurements at various temperatures. Thermal inactivation of the pure enzyme followed first-order kinetics. The half-life (t1/2) of the pure enzyme at 50 °C, 60 °C, and 70 °C was 385, 231, and 154 min, respectively. Thermodynamic parameters (entropy and enthalpy) suggested that the protease was highly thermostable. This is the first report on the thermodynamic parameters of proteases produced by M. indicus. The novel protease appears to be particularly thermostable and may be important for industrial applications based on these thermodynamic properties.

Anticholinesterase Activity of Budmunchiamine Alkaloids Revealed by Comparative Chemical Profiling of Two Albizia spp., Molecular Docking and Dynamic Studies.

Alzheimer's disease remains a global health challenge and an unmet need requiring innovative approaches to discover new drugs. The current study aimed to investigate the inhibitory activity of Albizia lucidior and Albizia procera leaves against acetylcholinesterase enzyme in vitro and explore their chemical compositions. Metabolic profiling of the bioactive plant, A. lucidior, via UHPLC/MS/MS-based Molecular Networking highlighted the richness of its ethanolic extract with budmunchiamine alkaloids, fourteen budmunchiamine alkaloids as well as four new putative ones were tentatively identified for the first time in A. lucidior. Pursuing these alkaloids in the fractions of A. lucidior extract via molecular networking revealed that alkaloids were mainly concentrated in the ethyl acetate fraction. In agreement, the alkaloid-rich fraction showed the most promising anticholinesterase activity (IC50 5.26 µg/mL) versus the ethanolic extract and ethyl acetate fraction of A. lucidior (IC50 24.89 and 6.90 µg/mL, respectively), compared to donepezil (IC50 3.90 µg/mL). Furthermore, deep in silico studies of tentatively identified alkaloids of A. lucidior were performed. Notably, normethyl budmunchiamine K revealed superior stability and receptor binding affinity compared to the two used references: donepezil and the co-crystallized inhibitor (MF2 700). This was concluded based on molecular docking, molecular dynamics simulations and molecular mechanics generalized born/solvent accessibility (MM-GBSA) calculations.

All-Solid-State Potentiometric Platforms Modified with a Multi-Walled Carbon Nanotubes for Fluoxetine Determination.

Novel cost-effective screen-printed potentiometric platforms for simple, fast, and accurate assessment of Fluoxetine (FLX) were designed and characterized. The potentiometric platforms integrate both the FLX sensor and the reference Ag/AgCl electrode. The sensors were based on the use of 4'-nitrobenzo-15-crown-5 (ionophore I), dibenzo-18-crown-6 (ionophore II), and 2-hydroxypropyl-ß-cyclodextrin (2-HP-ß-CD) (ionophore III) as neutral carriers within a plasticized PVC matrix. Multiwalled carbon nanotubes (MWCNTs) were used as a lipophilic ion-to-electron transducing material and sodium tetrakis [3,5-bis(trifluoromethyl)phenyl] borate (NaTFPB) was used as an anionic excluder. The presented platforms revealed near-Nernstian potentiometric response with slopes of 56.2 ± 0.8, 56.3 ± 1.7 and 64.4 ± 0.2 mV/decade and detection limits of 5.2 × 10-6, 4.7 × 10-6 and 2.0 × 10-7 M in 10 mM Tris buffer solution, pH 7 for sensors based on ionophore I, II, and III, respectively. All measurements were carried out in 10 mM tris buffer solution at pH 7.0. The interfacial capacitance before and after insertion of the MWCNTs layer was evaluated for the presented sensors using the reverse-current chronopotentiometry. The sensors were introduced for successful determination of FLX drug in different pharmaceutical dosage forms. The results were compared with those obtained by the standard HPLC method. Recovery values were calculated after spiking fixed concentrations of FLX in different serum samples. The presented platforms can be potentially manufacturable at large scales and provide a portable, rapid, disposable, and cost-effective analytical tool for measuring FLX.

New Potentiometric Screen-Printed Platforms Modified with Reduced Graphene Oxide and Based on Man-Made Imprinted Receptors for Caffeine Assessment.

Caffeine is a psychoactive drug that is administered as a class II psychotropic substance. It is also considered a component of analgesics and cold medicines. Excessive intake of caffeine may lead to severe health damage or drug addiction problems. The assessment of normal caffeine consumption from abusive use is not conclusive, and the cut-off value for biological samples has not been established. Herein, new cost-effective and robust all-solid-state platforms based on potentiometric transduction were fabricated and successfully utilized for caffeine assessment. The platforms were modified with reduced graphene oxide (rGO). Tailored caffeine-imprinted polymeric beads (MIPs) based on methacrylic acid (MAA) and ethylene glycol dimethacrylate (EGDMA) were prepared, characterized, and used as recognition receptors in the presented potentiometric sensing devices. In 50 mM MES buffer, the sensors exhibited a slope response of 51.2 ± 0.9 mV/decade (n = 6, R2 = 0.997) over the linear range of 4.5 × 10−6−1.0 × 10−3 M with a detection limit of 3.0 × 10−6 M. They exhibited fast detection of caffeinium ions with less than 5 s response time (<5 s). The behavior of the presented sensors towards caffeinium ions over many common organic and inorganic cations was evaluated using the modified separate solution method (MSSM). Inter-day and intra-day precision for the presented analytical device was also evaluated. Successful applications of the presented caffeine sensors for caffeine determination in commercial tea and coffee and different pharmaceutical formulations were carried out. The data obtained were compared with those obtained by the standard liquid chromatographic approach. The presented analytical device can be considered an attractive tool for caffeine determination because of its affordability and vast availability, particularly when combined with potentiometric detection.