Mixed Inhibitor Research Articles

New drug combination regimen based on pharmacokinetic characteristics—Erdafitinib combined with sertraline or duloxetine

The aim of this study is to investigate novel strategies for reducing adverse reactions caused by erdafitinib through a drug combination based on its pharmacokinetic characteristics. The spectrum and characterizations of drugs that can inhibit the metabolism of erdafitinib are examined both in vitro and in vivo. The efficacy of combination regimens are then evaluated using subcutaneous xenograft tumor models. The results demonstrated that sertraline and duloxetine, out of more than 100 screened drugs, inhibited the metabolism of erdafitinib through mixed and non-competitive inhibition, respectively. This inhibition primarily occurred via the CYP2C9 and CYP2D6 pathways. The primary alleles of CYP2C9 and CYP2D6 not only determine the metabolic characteristics of erdafitinib but also influence the strength of drug-drug interactions. Co-administration of sertraline or duloxetine with erdafitinib in rats and mice resulted in nearly a three-fold increase in the blood exposure of erdafitinib and its major metabolite M6. When sertraline or duloxetine was combined with 1/3 of the erdafitinib dosage, the anti-proliferative and pro-apoptotic effects on SNU-16 xenografts were comparable to those of the original full dose of erdafitinib. However, the combination regimen significantly mitigated hyperphosphatemia, retinal damage, intestinal villus damage, and gut microbiome dysbiosis. This study utilized pharmacokinetic methods to propose a new formulation of erdafitinib combined with sertraline or duloxetine. The findings suggest that this combination has potential for clinical co-administration based on a database analysis, thereby providing a novel strategy for anti-tumor treatment with fibroblast growth factor receptor (FGFR) inhibitors.

Assessment of Warionia saharea Essential Oil as a Green Corrosion Inhibitor for Mild Steel in HCl: Experimental and Computational Studies

The objective of this research work is the study of the inhibitory effect of Warionia saharea essential oil (WSEO) on the corrosion of mild steel (MS) in molar HCl solution, employing both experimental and theoretical methods. This inhibitory effect (IE) has been evaluated by using a combination of weight loss measurements (LW) and various electrochemical methods, such as open circuit potential (OCP), potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS) experiments. The LW results indicated that IE increased with inhibitor concentration, reaching 83.34% at 3.00 g/L. The PDP analysis suggested that WSEO functions as a mixed inhibitor, while in the EIS results the Rct values increased with inhibitor concentration to reach 165.8 Ω cm2 at 2.00 g/L, suggesting a defensive film formation by WSEO molecules over the metallic surface. The thermodynamic study demonstrated that the WSEO molecules adsorption on the MS surface followed a Langmuir isotherm, involving mixed physical and chemical (physicochemical) adsorption on the MS surface. Theoretical methods, including density functional theory (DFT) and molecular dynamics (MD) simulations, were employed to elucidate the inhibition mechanisms of the three main components of WSEO. The quantum chemical analysis, using density functional theory (DFT) and molecular dynamics (MD) simulations, showed a low ΔEgap value of 6.30 eV and a low adsorption energy (Eads) value on an Fe (110) substrate of −258 Kcal/mol for (E)-Nerolidol, indicating the significant contribution of this molecule to the overall corrosion inhibition effect of WSEO. The scanning electron microscope (SEM) analysis verified the presence of a protective film formed by the inhibitor on the MS surface. This study highlights the potential of WSEO as a sustainable and green corrosion inhibitor in acidic environments.

Investigation of biodegradable surfactant as a corrosion inhibitor to the cold rolled steel in the membrane separation device process

The membrane process is an effective way to realize resource reutilization. Most membrane devices are made of cold-roll steel (CRS), which is easy to corrode when operating in acid conditions. Herein, the biodegradable surfactant dodecyl dimethyl betaine (BS-12) was used as the inhibitor to protect the CRS in the trichloroacetic acid (TCA) solution. The long-term stability membrane tests showed that adding BS-12 will not harm the membrane performance. The weight loss experiments proved that adding BS-12 with trace amount (10 mg·L−1) endowed the CRS with good inhibition efficiency (95.3 %). The electrochemical tests indicated that the mixed inhibitor- BS-12 works by inhibiting the anode and cathode simultaneously, and the polarization resistance increased to 21 times. The SEM, AFM, and CLSM tests proved that adding BS-12 enabled the CRS surface to remain stable. The FTIR and XPS tests proved that BS-12 adsorbed on the CRS surface via physical and chemical adsorption. The theoretical calculations proved the horizontal adsorption of BS-12 on the CRS surface and the existence of the electron transfer within the BS-12 and CRS. The BS-12 showed great potential in the CRS inhibition of the membrane separation and purification processing.

The antihyperuricemic and nephroprotective effect of puerarin by reducing uric acid level and exerting anti‐inflammatory activity

AbstractHyperuricemia (HUA) is a common metabolic disease and kidney injury is one of its main complications. As a typical natural flavonoid, puerarin (PEA) has a range of pharmacological activity but the antihyperuricemic mechanism of PEA has not been reported. Herein, the inhibitory activity of PEA against xanthine oxidase (XOD) was evaluated by in vitro enzymatic reaction, and kinetic analysis, the antihyperuricemic activity, and nephroprotective effect of PEA were studied in HUA mice. The enzymatic reaction showed that the inhibitory effect of PEA (half maximal inhibitory concentration [IC50] = 4.39 µmol/L) on XOD was at the same level as allopurinol (IC50 = 4.05 µmol/L), and kinetic analysis indicated that PEA was a mixed competitive inhibitor. In vivo studies demonstrated that PEA exhibited excellent antihyperuricemic activity by inhibiting XOD and urate transporter 1 (URAT1), to reduce uric acid level. At the same time, PEA reduced the level of inflammatory cytokines and exerted significant nephroprotective effect through anti‐inflammatory activity. Molecular docking indicated that PEA closely bind to both XOD and URAT1, which had the potential to become an inhibitor of XOD and URAT1. In summary, PEA has important application value in developing novel functional food and medicine for the treatment of HUA and its complications.

Inhibitory effect of human indoleamine 2,3-dioxygenase 1 (hIDO1) by kazinols of 1,3-diphenylpropane derivatives

This study focused on identifying and characterizing 1,3-diphenylpropane derivatives from flavonoids that inhibit human indoleamine 2,3-dioxygenase 1 (hIDO1) enzymes, which play a role in immune regulation and are associated with various diseases. A series of isolated metabolites (1–7) demonstrated modest to high inhibition of hIDO1, with binding degree values ranging from 26.31 to 72.17%. In particular, during a target-based screening of natural products using hIDO1, kazinol J (6, a 1,3-diphenylpropane derivative) was found to potently inhibit hIDO1, with a binding degree of 72.17% at 1 ppm. Kazinol J (6) showed concentration-dependent and mixed inhibition kinetics and achieved slow and time-dependent inhibition of hIDO1. Additionally, docking simulations were performed to evaluate the inhibitory potential and binding interactions of the compounds with hIDO1. These findings suggest that these 1,3-diphenylpropane derivatives can serve as therapeutic agents for conditions involving hIDO1 dysregulation, such as cancer, autoimmune disorders, and infectious diseases.

Discovery of natural anthraquinones as potent inhibitors against pancreatic lipase: structure-activity relationships and inhibitory mechanism

Obesity is acknowledged as a significant risk factor for various metabolic diseases, and the inhibition of human pancreatic lipase (hPL) can impede lipid digestion and absorption, thereby offering potential benefits for obesity treatment. Anthraquinones is a kind of natural and synthetic compounds with wide application. In this study, the inhibitory effects of 31 anthraquinones on hPL were evaluated. The data shows that AQ7, AQ26, and AQ27 demonstrated significant inhibitory activity against hPL, and exhibited selectivity towards other known serine hydrolases. Then the structure-activity relationship between anthraquinones and hPL was further analysed. AQ7 was found to be a mixed inhibition of hPL through inhibition kinetics, while AQ26 and AQ27 were effective non-competitive inhibition of hPL. Molecular docking data revealed that AQ7, AQ26, and AQ27 all could associate with the site of hPL. Developing hPL inhibitors for obesity prevention and treatment could be simplified with this novel and promising lead compound.

Rutin of Moringa oleifera as a potential inhibitor to Agaricus bisporus tyrosinase as revealed from the molecular dynamics of inhibition

Tyrosinase is a binuclear copper-containing enzyme that catalyzes the conversation of monophenols to diphenols via o-hydroxylation and then the oxidation of o-diphenols to o-quinones which is profoundly linked to eukaryotic melanin synthesis and fruits browning. The hyperpigmentation due to unusual tyrosinase activity has gained growing health concern. Plants and their metabolites are considered promising and effective sources for potent antityrosinase enzymes. Hence, searching for potent, specific tyrosinase inhibitor from different plant extracts is an alternative approach in regulating overproduction of tyrosinase. Among the tested extracts, the hydro-alcoholic extract of Moringa oleifera L. leaves displayed the potent anti-tyrosinase activity (IC50 = 98.93 µg/ml) in a dose-dependent manner using L-DOPA as substrate; however, the kojic acid showed IC50 of 88.92 µg/ml. The tyrosinase-diphenolase (TYR-Di) kinetic analysis revealed mixed inhibition type for the Ocimum basilicum L. and Artemisia annua L. extracts, while the Coriandrum sativum L. extract displayed a non-competitive type of inhibition. Interestingly, the extract of Moringa oleifera L. leaves exhibited a competitive inhibition, low inhibition constant of free enzyme (Kiiapp\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\ ext{K}}_{\ ext{ii}}^{\ ext{app}}$$\\end{document}) value and no Pan-Assay Interfering Substances, hinting the presence of strong potent inhibitors. The major putative antityrosinase compound in the extract was resolved, and chemically identified as rutin based on various spectroscopic analyses using UV–Vis, FTIR, mass spectrometry, and 1H NMR. The in silico computational molecular docking has been performed using rutin and A. bisporus tyrosinase (PDB code: 2Y9X). The binding energy of the predicted interaction between tropolone native ligand, kojic acid, and rutin against 2Y9X was respectively − 5.28, − 4.69, and − 7.75 kcal/mol. The docking simulation results revealed the reliable binding of rutin to the amino acid residues (ASN260, HIS259, SER282) in the tyrosinase catalytic site. Based on the developed results, rutin extracted from M. oleifera L. leaves has the capability to be powerful anti-pigment agent with a potential application in cosmeceutical area. In vivo studies are required to unravel the safety and efficiency of rutin as antityrosinase compound.

In-depth study of a newly synthesized imidazole derivative as an eco-friendly corrosion inhibitor for mild steel in 1 M HCl: Theoretical, electrochemical, and surface analysis perspectives

The present study is concerned with the corrosion inhibition and adsorption behaviour of a series of novel imidazole derivatives. The compounds under investigation are 5,5-diphenyl-3-propyl-2-(propylthio)-3,5-dihydro-4 H-imidazol-4-one (AM3) and 3-allyl-2-(allylthio)-5,5-diphenyl-3,5-dihydro-4 H-imidazol-4-one (AM6). The objective of this study is to evaluate the efficacy of 5,5-diphenyl-3,5-dihydro-4 H-imidazol-4-one (AM6) as a corrosion inhibitor on mild steel immersed in a 1.0 M hydrochloric acid medium. This comprehensive study assesses the efficacy of these derivatives through a range of electrochemical and spectroscopic analysis techniques. Additionally, polarisation curves, electrochemical impedance spectroscopy and advanced computer simulations were employed to evaluate the efficacy and inhibition mechanism of imidazole derivatives, thereby facilitating a more profound understanding of their anticorrosive capacity. The results obtained from potentiodynamic polarisation (PDP), electrochemical frequency modulation (EFM) and electrochemical impedance spectroscopy (EIS) measurements demonstrate that the inhibition efficiency increases with increasing imidazole derivative concentration. Conversely, an inverse relationship is observed between inhibition efficiency and temperature. The thermodynamic parameters ΔG°_ads and ΔH°_ads corroborate the conclusion that the adsorption process is predominantly chemical in nature. Scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX) and X-ray photoelectron spectroscopy (XPS) were employed to characterise the surface morphology. The maximum protection afforded by imidazole derivatives was 95.2 % and 93 % for compounds AM3 and AM6, respectively. Polarisation curves indicated that imidazole derivatives exhibited mixed inhibition behaviour. Surface analysis demonstrated that imidazole derivatives were effectively adsorbed onto the carbon surface, thereby significantly reducing acid damage. This finding was corroborated by DFT calculations, as well as Monte Carlo (MC) and molecular dynamics (MD) simulations. These simulations provided a comprehensive insight into the adsorption of imidazole and its protonated form onto the carbon surface, offering valuable insight into the corrosion inhibition mechanism.

Synthesis and anti-ureolitic activity of Biginelli adducts derived from formylphenyl boronic acids

Urease is a metalloenzyme that contains two Ni(II) ions in its active site and catalyzes the hydrolysis of urea into ammonia and carbon dioxide. The development of effective urease inhibitors is crucial not only for mitigating nitrogen losses in agriculture but also for offering an alternative treatment against infections caused by resistant pathogens that utilize urease as a virulence factor. This study focuses on synthesizing and investigating the urease inhibition potential of Biginelli Adducts bearing a boric acid group. An unsubstituted or hydroxy-substituted boronic group in the Biginelli adducts structure enhances the urease inhibitory activity. Biophysical and kinetics studies revealed that the best Biginelli adduct (4e; IC50 = 132 ± 12 µmol/L) is a mixed inhibitor with higher affinity to the urease active site over an allosteric one. Docking studies confirm the interactions of 4e with residues essential for urease activity and demonstrate its potential to coordinate with the nickel atoms through the oxygen atoms of carbonyl or boronic acid groups. Overall, the Biginelli adduct 4e shows great potential as an additive for developing enhanced efficiency fertilizers and/or for medical applications.

Food additive salicylates inhibit human and rat placental 3β-hydroxysteroid dehydrogenase: 3D-QSAR and in silico analysis

The use of salicylates as flavoring agents in food and beverages is common, but their potential to disrupt the endocrine system remains unclear. Human placental 3β-hydroxysteroid dehydrogenase 1 (h3β-HSD1) plays a role in progesterone synthesis and is the potential target. This study evaluated the inhibition of 13 salicylates on h3β-HSD1, structure-activity relationship (SAR) and compared with rat placental homolog r3β-HSD4. Salicylates inhibited h3β-HSD1, depending on carbon chain number in the alcohol moiety and the IC50 values for hexyl, ethylhexyl, homomenthyl, and menthyl salicylates were 53.27, 15.78, 2.35, and 2.31 μM, as mixed inhibitors, respectively, while methyl to benzyl salicylates were ineffective at 100 μM. Interestingly, only hexyl salicylate inhibited r3β-HSD4 with IC50 of 31.05 μM. Bivariate analysis revealed a negative correlation between IC50 and hydrophobicity (LogP), molecular weight, heavy atoms, and carbon number in the alcohol moiety against h3β-HSD1. Docking analysis demonstrated that these salicylates bind to cofactor binding sites or between the steroid and cofactor binding sites. Additionally, 3D-QSAR showed distinct binding via hydrogen bond donors and hydrophobic regions. In conclusion, the inhibition of h3β-HSD1 by salicylates appears to be dependent on factors such as LogP, molecular weight, heavy atoms, and carbon-chain length and there is species-dependent inhibition sensitivity.

Azoles as corrosion inhibitors in alkaline medium for ruthenium chemical mechanical planarization applications:Electrochemical and theoretical analysis

The adsorption performance and inhibition mechanism of azoles; Imidazole (IMD), 1, 2, 4-Triazole (TAZ), and 1, 2, 3-Benzotriazole (BTAH) inhibitors on ruthenium (Ru) at 9 pH, were investigated in this study using electrochemical techniques and density functional theory (DFT) simulations. The electrochemical data demonstrate that the three azole compounds being investigated are mixed type corrosion inhibitors with anodic predominance, and the order of corrosion inhibition efficiency for Ru is BTAH > TAZ > IMD. The azole compounds suppress the metal dissolution reaction rate by adhering on to the Ru surface and nature of adsorption (combined physisorption and chemisorption) is explained via Langmuir adsorption isotherm model. The increase in contact angle on the Ru surface verified the successful adsorption of the three organic inhibitors on the Ru surface. Furthermore, the suppression of corrosion reaction kinetics is validated with field emission scanning electron microscopy (FESEM) images. The results of quantum chemistry calculations indicate that the corrosion inhibition effect of BTAH is superior to that of IMD and TAZ. Further, using molecular dynamics modelling, the reliable configuration of the organic inhibitor molecules on the Ru (001) surface in aqueous medium was investigated and the total adsorption energy was computed.

Electric stimulation mitigated the mixed microplastic inhibition to anaerobic digestion during wastewater treatment

The presence of mixed microplastics (MPs) in anaerobic wastewater treatment processes has been shown to impede fermentation performance by suppressing microbial activity. Microbial electrosynthesis (MES), with its extensive potential, offers a promising solution for refractory substances management and methane recovery, achieved through the enhancement of microbial metabolism and interspecies electron transfer. This study, therefore, delves into the functional impacts and the microbial response to MES in the remediation of wastewater contaminated with mixed-MPs. Results indicated that mixed-MPs could inhibit methane production (−52.38%) and substance removal (−26.59%), and MES could effectively mitigate this inhibitory effect (−22.86%, −19.01%). Concurrently, MES also boosts enzymatic activities pivotal for electron transfer, such as cytochrome c and nicotinamide adenine dinucleotide (NADH), as well as those linked to energy metabolism like adenosine triphosphate (ATP). Furthermore, MES bolsters microbial resistance to mixed-MPs, as evidenced by an increase in extracellular polymeric substances (EPS), albeit with a minor rise in reactive oxygen species (ROS) production and lactate dehydrogenase (LDH) release. Correspondingly, electric stimulation promoted the enrichment of functional microorganisms associated with fermentation, acetate production, electrogenesis, and methanogenesis, and stimulated elevated expression levels of genes related to methane metabolism. Notably, the Methanothrix-mediated acetoclastic pathway emerges as the predominant methanogenic route, succeeded by the Methanobacterium-driven hydrogenotrophic pathway. Lastly, the study underscores the supportive role of applied voltage and carriers in energy metabolism and substance transport, which are associated with methanogenesis. Overall, MES demonstrates efficacy in mitigating the biotoxicity induced by mixed-MPs exposure and in enhancing anaerobic wastewater treatment and methane recovery.

Quercetin slow-release system delays starch digestion via inhibiting transporters and enzymes

This study investigates the potential of a quercetin-based emulsion system to moderate starch digestion and manage blood glucose levels, addressing the lack of in vivo research. By enhancing quercetin bioaccessibility and targeting release in the small intestine, the emulsion system demonstrates significant inhibition of starch digestion and glucose spikes through both in vitro and in vivo experiments. The system inhibits α-amylase and α-glucosidase via competitive and mixed inhibition mechanisms, primarily involving hydrogen bonds and van der Waals forces, leading to static fluorescence quenching. Additionally, this system downregulates the protein expression and gene transcription of SGLT1 and GLUT2. These findings offer a novel approach to sustaining glucose equilibrium, providing a valuable foundation for further application of quercetin emulsion in food science.

The HIV latency reversing agent HODHBt inhibits the phosphatases PTPN1 and PTPN2.

Nonreceptor tyrosine phosphatases (NTPs) play an important role in regulating protein phosphorylation and have been proposed as attractive therapeutic targets for cancer and metabolic diseases. We have previously identified that 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) enhanced STAT activation upon cytokine stimulation, leading to increased reactivation of latent HIV and effector functions of NK and CD8 T cells. Here, we demonstrate that HODHBt interacted with and inhibited the NTPs PTPN1 and PTPN2 through a mixed inhibition mechanism. We also confirm that PTPN1 and PTPN2 specifically controlled the phosphorylation of different STATs. The small molecule ABBV-CLS-484 (AC-484) is an active site inhibitor of PTPN1 and PTPN2 currently in clinical trials for advanced solid tumors. We compared AC-484 and HODHBt and found similar effects on STAT5 and immune activation, albeit with different mechanisms of action leading to varying effects on latency reversal. Our studies provide the first specific evidence to our knowledge that enhancing STAT phosphorylation via inhibition of PTPN1 and PTPN2 is an effective tool against HIV.

Weight loss, electrochemical measurements and DFT studies on corrosion inhibition by 7-mercapto-4-methylcoumarin

Corrosion becomes a severe problem in several sectors due to its various effects. The present work focusing for corrosion inhibition efficiency of mild steel in 1 M HCl using 7-mercapto-4-methylcoumarin (MMC) through experimental and theoretical methods. Thus, the key goal is to understand to what extents MMC is efficient in avoiding corrosion in various situations. With this end in view, electrochemical impedance spectroscopy (EIS), dynamic polarization (DP) test and weight loss measurements were carried out. The outcomes showed the fact that corrosion mitigation efficiency was directly proportional to the concentration MMC but it was negatively proportional to temperature. The highest inhibition efficiency, up to the 95.8 %, was demonstrated at an inhibitor concentration of 0.5 mM. Based on Langmuir adsorption isotherm the wear properties of the mild steel indicated a mixed passive nature during MMC interactions. Additionally, quantum chemical calculations, including density functional theory (DFT), were achieved to determine the MMC molecular structure and its inhibition efficiency relationships. Key parameters such as the energy gap (Egap), EHOMO, ELUMO, hardness (η), softness, electronegativity (χ), and electron fraction transitions (ΔN) were also determine. The results from these computations were confirmed with the experimental results, confirming the mixed inhibition characteristics of MMC. The variation in activation energy in the presence of tested inhibitor further validated its effective as a corrosion inhibitor, with comprehensive insights into its potential industrial usages.

Anticorrosive activity of Melothria perpusilla: A renewable and sustainable inhibitor

Anticorrosive activity of Melothria perpusilla extract on mild steel in H2SO4 was examined by weight loss, potentiodynamic polarization and electrochemical impedance spectroscopy methods. The results revealed that mild steel corrosion was effectively controlled by the extract with 99.4 % efficiency at 3000mg/L concentration. The efficiency was improved with higher extract concentration but decreased as the temperature increased. The Tafel plots and its corrosion potential value (<85 mV) inferred that Melothria perpusilla acts as a mixed type inhibitor. Adsorption of phytochemicals onto the surface of mild steel is the primary factor in reducing corrosion. The increase in activation energy for adsorption from 22.73 kJ mol−1 in acid to 133.74 kJ mol−1 in extract's presence confirms the active role of phytochemicals in adsorption process. The increase in charge transfer resistance from 3.21 Ω cm2 in acid to 369.2 Ω cm2 in extract's presence, coupled with a decrease in double layer capacitance in the EIS investigation, suggests that a charge transfer mechanism is active at the mild steel-solution interface. Gas chromatography-Mass spectroscopy revealed the presence of five major phytochemicals along with other organic compounds in the extract. Fourier transform infrared and UV–visible spectroscopies indicated the active functional moieties (-COOH, –CONH2, -C-O-C-, –C=C- and long chain alkyl groups) are involved in the inhibition. Scanning electron microscopy confirmed the existence of shielding film of phytochemicals on mild steel. Density functional theory validated the inhibitory properties of the constituents. Therefore, it is concluded that Melothria perpusilla is an efficient green inhibitor in acidic condition.

BACE1 inhibitors from the fruits of Alpinia oxyphylla have efficacy to treat T2DM-related cognitive disorder

The fruits of Alpinia oxyphylla (Alpiniae Oxyphyllae Fructus, AOF) are one of the “Four Famous South Medicines” in China. In this study, beta-site amyloid protein precursor cleaving enzyme 1 (BACE1) was applied to explore the active components in AOF responsible for type 2 diabetes mellitus (T2DM)-related cognitive disorder. As a result, 24 compounds including three unreported ones (1, 3, 4) were isolated from AOF. Compound 1 is an unusual carbon‑carbon linked diarylheptanoid dimer, and compound 4 is the first case of 3,4-seco-eudesmane sesquiterpenoid with a 5/6-bicyclic skeleton. Four diarylheptanoids (3, 5–7), one flavonoid (9) and two sesquiterpenoids (14 and 20) showed BACE1 inhibitory activity, of which the most active 6 was revealed to be a non-competitive and anti-competitive mixed inhibitor. Docking simulation suggested that OH-4′ of 6 played important roles in maintaining activity by forming hydrogen bonds with Ser36 and Ile126 residues. Compounds 3, 5, 9 and 20 displayed neuroprotective effects against amyloid β (Aβ)-induced damage in BV2 cells. Mechanism study revealed that compounds 5 and 20 downregulated the expression of BACE1 and upregulated the expression of Lamp2 to exert effects. Thus, the characteristic diarylheptanoids and sesquiterpenoids in AOF had the efficacy to alleviate T2DM-related cognitive disorder by inhibiting BACE1 activity and reversing Aβ-induced neuronal damage.

Development of novel pyrazole-1,2,4-triazole derivatives as tyrosinase inhibitors: Design, preparation, mechanism of action and anti-browning application

Tyrosinase (Polyphenol oxidase), a key enzyme in enzymatic browning, is an attractive target for developing new anti-browning agents in the food industry. In this work, twenty pyrazole-1,2,4-triazole derivatives (3a-3n, 4a-4f) were synthesized and tested in vitro, most of compounds showed potent anti-tyrosinase activity. Of these, 3c (IC50 = 1.02 ± 0.08 μM) was found to be 14 folds stronger than kojic acid (IC50 = 14.74 ± 1.23 μM) and behaved as a mixed type inhibitor. Besides, the disappeared peak of dopaquinone in the HPLC assay intuitively validated the inhibitory effect of 3c. Copper ions chelating, fluorescence quenching and molecular docking assays showed that coordination with copper is the key to play a role. Furthermore, 3c exhibited excellent anti-browning ability for the Rosa roxburghii Tratt, the non-enzymatic browning experiment showed that 3c could prevent browning in non-enzymatic ways. It is suggested that these derivatives could serve as the leading compounds to find more efficient anti-browning agents in the future.

Insights into corrosion inhibition of aluminum in hydrochloric acid solutions using expired cephalosporins and klavox: Chemical, electrochemical and theoretical approaches

The inhibitory efficacy of two expired antibiotic drugs namely, cephalosporin and klavox against corrosion of aluminum in 1.0 M HCl solution was investigate utilizing potentiodynamic polarization (PDP) impedance spectroscopy (EIS) and weight reduction (WR) methodologies. It was discovered that the two expired drugs act as excellent inhibitors and the inhibition efficacy increases as the drug concentration increases and the temperature decreases. The inhibition efficacy reached 97.62 % and 99.42 % at 900 ppm of cephalosporin and klavox at 298 K, respectively. Expired drugs act as a mixed type inhibitor, controlling primarily the anodic and cathodic process, as evidenced by the PDP curves. According to EIS analysis, the charge transfer resistance values increased with increasing inhibitor concentration. The adsorption isotherm demonstrates that the expired drugs become active by physical adsorption on the Al surface, and their adsorption obeys the Langmuir isotherm. Through quantum chemistry calculations, the relationship between the inhibition properties and molecular structure was studied.

Dissecting molecular mechanisms underlying the inhibition of β-glucuronidase by alkaloids from Hibiscus trionum: Integrating in vitro and in silico perspectives

β-Glucuronidase, a crucial enzyme in drug metabolism and detoxification, represents a promising target for therapeutic intervention due to its potential to modulate drug pharmacokinetics and enhance therapeutic efficacy. Herein, we assessed the inhibitory potential of phytochemicals from Hibiscus trionum against β-glucuronidase. Grossamide and grossamide K emerged as the most potent β-glucuronidase inhibitors with IC50 values of 0.73 ± 0.03 and 1.24 ± 0.03 μM, respectively. The investigated alkaloids effectively inhibited β-glucuronidase-catalyzed PNPG hydrolysis through a noncompetitive inhibition mode, whereas steppogenin displayed a mixed inhibition mechanism. Molecular docking analyses highlighted grossamide and grossamide K as inhibitors with the lowest binding free energy, all compounds successfully docked into the same main binding site occupied by the reference drug Epigallocatechin gallate (EGCG). We explored the interaction dynamics of isolated compounds with β-glucuronidase through a 200 ns molecular dynamics (MD) simulation. Analysis of various MD parameters revealed that grossamide and grossamide K maintained stable trajectories and demonstrated significant energy stabilization upon binding to β-glucuronidase. Additionally, these compounds exhibited the lowest average interaction energies with the target enzyme. The MM/PBSA calculations further supported these findings, showing the lowest binding free energies for grossamide and grossamide K. These computational results are consistent with experimental data, suggesting that grossamide and grossamide K could be potent inhibitors of β-glucuronidase.