Oxidation of Styrene to Benzaldehyde Catalyzed by Schiff Base Functionalized Triazolylidene Ni(II) Complexes

Four new Schiff base functionalized 1,2,3-triazolylidene nickel complexes, [Ni-(L₁NHC)₂](PF₆)₂; 3, [Ni-(L₂NHC)₂](PF₆)₂; 4, [Ni-(L₃NHC)](PF₆)₂; 7 and [Ni-(L₄NHC)](PF₆)₂; 8, (where L₁NHC = (E)-3-methyl-1-propyl-4-(2-(((2-(pyridin-2-yl)ethyl)imino)methyl)phenyl)-1H-1,2,3-triazol-3-ium hexafluorophosphate(V), 1, L₂NHC = (E)-3-methyl-4-(2-((phenethylimino)methyl)phenyl)-1-propyl-1H-1,2,3-triazol-3-ium hexafluorophosphate(V), 2, L₃NHC = 4,4′-(((1E)-(ethane-1,2-diylbis(azanylylidene))bis(methanylylidene))bis(2,1-phenylene))bis(3-methyl-1-propyl-1H-1,2,3-triazol-3-ium) hexafluorophosphate(V), 5, and L₄NHC = 4,4′-(((1E)-(butane-1,4-diylbis(azanylylidene))bis(methanylylidene))bis(2,1-phenylene))bis(3-methyl-1-propyl-1H-1,2,3-triazol-3-ium) hexafluorophosphate(V), 6), were synthesised and characterised by a variety of spectroscopic methods. Square planar geometry was proposed for all the nickel complexes. The catalytic potential of the complexes was explored in the oxidation of styrene to benzaldehyde, using hydrogen peroxide as a green oxidant in the presence of acetonitrile at 80 °C. All complexes showed good catalytic activity with high selectivity to benzaldehyde. Complex 3 gave a conversion of 88% and a selectivity of 70% to benzaldehyde in 6 h. However, complexes 4 and 7–8 gave lower conversions of 48–74% but with higher (up to 90%) selectivity to benzaldehyde. Results from kinetics studies determined the activation energy for the catalytic oxidation reaction as 65 ± 3 kJ/mol, first order in catalyst and fractional order in the oxidant. Results from UV-visible and CV studies of the catalytic activity of the Ni-triazolylidene complexes on styrene oxidation did not indicate any clear possibility of generation of a Ni(II) to Ni(III) catalytic cycle.     

Sarcorucinine-D Inhibits Cholinesterases and Calcium Channels: Molecular Dynamics Simulation and In Vitro Mechanistic Investigations

Acetylcholinesterase (AChE) inhibitors and calcium channel blockers are considered effective therapies for Alzheimer’s disease. AChE plays an essential role in the nervous system by catalyzing the hydrolysis of the neurotransmitter acetylcholine. In this study, the inhibition of the enzyme AChE by Sarcorucinine-D, a pregnane type steroidal alkaloid, was investigated with experimental enzyme kinetics and molecular dynamics (MD) simulation techniques. Kinetics studies showed that Sarcorucinine-D inhibits two cholinesterases—AChE and butyrylcholinesterase (BChE)—noncompetitively, with K_i values of 103.3 and 4.66 µM, respectively. In silico ligand-protein docking and MD simulation studies conducted on AChE predicted that Sarcorucinine-D interacted via hydrophobic interactions and hydrogen bonds with the residues of the active-site gorge of AChE. Sarcorucinine-D was able to relax contractility concentration-dependently in the intestinal smooth muscles of jejunum obtained from rabbits. Not only was the spontaneous spasmogenicity inhibited, but it also suppressed K⁺-mediated spasmogenicity, indicating an effect via the inhibition of voltage-dependent Ca²⁺ channels. Sarcorucinine-D could be considered a potential lead molecule based on its properties as a noncompetitive AChE inhibitor and a Ca²⁺ channel blocker.     

In Vitro Evaluation of Curcumin Encapsulation in Gum Arabic Dispersions under Different Environments

Biopolymers, especially polysaccharides (e.g., gum Arabic), are widely applied as drug carriers in drug delivery systems due to their advantages. Curcumin, with high antioxidant ability but limited solubility and bioavailability in the body, can be encapsulated in gum Arabic to improve its solubility and bioavailability. When curcumin is encapsulated in gum Arabic, it is essential to understand how it works in various conditions. As a result, in Simulated Intestinal Fluid and Simulated Gastric Fluid conditions, we investigated the potential of gum Arabic as the drug carrier of curcumin. This study was conducted by varying the gum Arabic concentrations, i.e., 5, 10, 15, 20, 30, and 40%, to encapsulate 0.1 mg/mL of curcumin. Under both conditions, the greater the gum Arabic concentration, the greater the encapsulation efficiency and antioxidant activity of curcumin, but the worse the gum Arabic loading capacity. To achieve excellent encapsulation efficiency, loading capacity, and antioxidant activity, the data advises that 10% is the best feasible gum Arabic concentration. Regarding the antioxidant activity of curcumin, the findings imply that a high concentration of gum Arabic was effective, and the Simulated Intestinal Fluid brought an excellent surrounding compared to the Simulated Gastric Fluid solution. Moreover, the gum Arabic releases curcumin faster in the Simulated Gastric Fluid condition.     

In Silico Analysis of PORD Mutations on the 3D Structure of P450 Oxidoreductase

Cytochrome P450 oxidoreductase (POR) is a membrane-bound flavoprotein that helps in transferring electrons from its NADPH domain to all cytochrome P450 (CYP450) enzymes. Mutations in the POR gene could severely affect the metabolism of steroid hormones and the development of skeletal muscles, a condition known as Cytochrome P450 oxidoreductase deficiency (PORD). PORD is associated with clinical presentations of disorders of sex development, Antley and Bixler’s syndrome (ABS), as well as an abnormal steroid hormone profile. We have performed an in silico analysis of POR 3D X-ray protein crystal structure to study the effects of reported mutations on the POR enzyme structure. A total of 32 missense mutations were identified, from 170 PORD patients, and mapped on the 3D crystal structure of the POR enzyme. In addition, five of the missense mutations (R457H, A287P, D210G, Y181D and Y607C) were further selected for an in-depth in silico analysis to correlate the observed changes in POR protein structure with the clinical phenotypes observed in PORD patients. Overall, missense mutations found in the binding sites of POR cofactors could lead to a severe form of PORD, emphasizing the importance of POR cofactor binding domains in transferring electrons to the CYP450 enzyme family.     

Microscale Thermophoresis and Molecular Modelling to Explore the Chelating Drug Transportation in the Milk to Infant

The microscale thermophoresis (MST) technique was utilized to investigate lactoferrin–drug interaction with the iron chelator, deferiprone, using label-free system. MST depends on the intrinsic fluorescence of one interacting partner. The results indicated a significant interaction between lactoferrin and deferiprone. The estimated binding constant for the lactoferrin–deferiprone interaction was 8.9 × 10⁻⁶ ± 1.6, SD, which is to be reported for the first time. Such significant binding between lactoferrin and deferiprone may indicate the potentiation of the drug secretion into a lactating mother’s milk. The technique showed a fast and simple approach to study protein–drug interaction while avoiding complicated labeling procedures. Moreover, the binding behavior of deferiprone within the binding sites of lactoferrin was investigated through molecular docking which reflected that deferiprone mediates strong hydrogen bonding with ARG121 and ASP297 in pocket 1 and forms H-bond and ionic interaction with ASN640 and ASP395, respectively, in pocket 2 of lactoferrin. Meanwhile, iron ions provide ionic interaction with deferiprone in both of the pockets. The molecular dynamic simulation further confirmed that the binding of deferiprone with lactoferrin brings conformational changes in lactoferrin that is more energetically stable. It also confirmed that deferiprone causes positive correlation motion in the interacting residues of both pockets, with strong negative correlation motion in the loop regions, and thus changes the dynamics of lactoferrin. The MM-GBSA based binding free energy calculation revealed that deferiprone exhibits ∆G TOTAL of −63,163 kcal/mol in pocket 1 and −63,073 kcal/mol in pocket 2 with complex receptor–ligand difference in pocket 1 and pocket 2 of −117.38 kcal/mol and −111.54 kcal/mol, respectively, which in turn suggests that deferiprone binds more strongly in the pocket 1. The free energy landscape of the lactoferrin–deferiprone complex also showed that this complex remains in a high energy state that confirms the strong binding of deferiprone with the lactoferrin. The current research concluded that iron-chelating drugs (deferiprone) can be transported from the mother to the infant in the milk because of the strong attachment with the lactoferrin active pockets.     

Evaluation of Phytochemistry and Pharmacological Properties of Alnus nitida

In the current study, the anti-inflammatory and analgesic potential of Alnus nitida (leaves and fruits) was evaluated in the Sprague-Dawley rat. Traditionally, A. nitida was used for the treatment of inflammatory ailments. However, A. nitida leaves and fruits have not been yet reported regarding any potential medicinal effects. Leaves/fruits of A. nitida were extracted with methanol and fractionated to attain n-hexane, chloroform, ethyl acetate and aqueous fractions. These extracts were then evaluated for in vivo analgesic and anti-inflammatory potential. For in vivo anti-inflammatory activity, carrageenan-induced paw edema assay, Freunds’ complete adjuvant-induced edema, xylene-induced ear edema and histamine-induced paw edema models were used in rats, which showed significant (p < 0.01) reduction (70–80%) in edema in comparison of inflammatory controls. On other hand, for the analgesic assessment, hot plate assay and acetic acid-induced writhing tests were used, which showed a significant (p < 0.01) rise in latency time (40–60%) as compared with pain-induced controls. These results were comparable with standard drugs in a concentration-dependent manner and no mortality or toxicity was observed during all experiments. Then, for the identification of chemical constituents gas chromatography–mass spectrometry (GC-MS) analysis was performed, which indicated the presence of neophytadiene, 3,7,11,15-Tetramethyl-2-hexadecen-1-ol, phytol and vitamin E, justifying the use of A. nitida to treat inflammatory disorders.     

Friedelin Attenuates Neuronal Dysfunction and Memory Impairment by Inhibition of the Activated JNK/NF-κB Signalling Pathway in Scopolamine-Induced Mice Model of Neurodegeneration

Oxidative stress (OS) and c-Jun N-terminal kinase (JNK) are both key indicators implicated in neuro-inflammatory signalling pathways and their respective neurodegenerative diseases. Drugs targeting these factors can be considered as suitable candidates for treatment of neuronal dysfunction and memory impairment. The present study encompasses beneficial effects of a naturally occurring triterpenoid, friedelin, against scopolamine-induced oxidative stress and neurodegenerative pathologies in mice models. The treated animals were subjected to behavioural tests i.e., Y-maze and Morris water maze (MWM) for memory dysfunction. The underlying mechanism was determined via western blotting, antioxidant enzymes and lipid profile analyses. Molecular docking studies were carried out to predict the binding modes of friedelin in the binding pocket of p-JNK protein. The results reveal that scopolamine caused oxidative stress by (1) inhibiting catalase (CAT), peroxidase enzyme (POD), superoxide dismutase (SOD), and reduced glutathione enzyme (GSH); (2) the up-regulation of thiobarbituric acid reactive substances (TBARS) in mice brain; and (3) affecting the neuronal synapse (both pre- and post-synapse) followed by associated memory dysfunction. In contrast, friedelin administration not only abolished scopolamine-induced oxidative stress, glial cell activation, and neuro-inflammation but also inhibited p-JNK and NF-κB and their downstream signaling molecules. Moreover, friedelin administration improved neuronal synapse and reversed scopolamine-induced memory impairment accompanied by the inhibition of β-secretase enzyme (BACE-1) to halt amyloidogenic pathways of amyloid-β production. In summary, all of the results show that friedelin is a potent naturally isolated neuro-therapeutic agent to reverse scopolamine-induced neuropathology, which is characteristic of Alzheimer’s disease.     

Novel Design of RNA Aptamers as Cancer Inhibitors and Diagnosis Targeting the Tyrosine Kinase Domain of the NT-3 Growth Factor Receptor Using a Computational Sequence-Based Approach

Aptamers, the nucleic acid analogs of antibodies, bind to their target molecules with remarkable specificity and sensitivity, making them promising diagnostic and therapeutic tools. The systematic evolution of ligands by exponential enrichment (SELEX) is time-consuming and expensive. However, regardless of those issues, it is the most used in vitro method for selecting aptamers. Therefore, recent studies have used computational approaches to reduce the time and cost associated with the synthesis and selection of aptamers. In an effort to present the potential of computational techniques in aptamer selection, a simple sequence-based method was used to design a 69-nucleotide long aptamer (mod_09) with a relatively stable structure (with a minimum free energy of −32.2 kcal/mol) and investigate its binding properties to the tyrosine kinase domain of the NT-3 growth factor receptor, for the first time, by employing computational modeling and docking tools.