Binding Interactions Research Articles

Synthesis and Characterization of Ester Derivatives of N-Phenylanthranilic Acid

N-Phenylanthranilic acid (fenamic acid) serves as the fundamental structure for synthesizing several non-steroidal anti-inflammatory drugs, antibacterial drugs and also functions as a modulator of membrane transport. To reduce the dose-related side effects of existing drugs, research is focussing to improve fenamic acid derivative solubility and bioavailability. A series of ester derivatives of N-phenylanthranilic acid (MB-1 to MB-5) viz. 2-(phenyl amino)methyl benzoate, 2-(phenyl amino)ethyl benzoate, 2-(phenyl amino)isopropyl benzoate,2-(phenyl amino)butyl benzoate and 2-(phenyl amino)phenyl benzoate were synthesized. The chemical structures and functional groups of these derivatives were confirmed using elemental analysis and spectral data. Furthermore, the derived compounds were evaluated for their antibacterial activity against Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram-positive) strains using the agar-well diffusion method followed by molecular docking studies to predict binding interactions of the synthesized compounds with DNA gyrase.

Design, Synthesis and Cholinesterase Inhibitory Activity of Novel 1,3,4-Thiadiazole Derivatives

Inhibition of the cholinesterases (AChE and BChE) plays a pivotal role in the symptomatic treatment of Alzheimer’s disease. The present study reports the synthesis and anticholinesterase activity of five novel thiadiazole analogs in search of anti-Alzheimer agents. The structures of the newly synthesized compounds were characterized using 1H NMR, 13C NMR and HRMS. Tested compounds inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes with IC50 values in the range of 8.250-20.382 μM and 14.143-0.986 μM, respectively. N-(4-Chlorophenyl)-2-[(5-(allylamino)-1,3,4-thiadiazol-2-yl)thio]-N-(3-nitrobenzyl)acetamide (6e) was determined as the most potent inhibitor against both tested enzymes when compared with standard drug tacrine. Molecular docking study was carried out to reveal the binding interactions between compound 6e and the active site of AChE

Novel hydrazide-hydrazone containing 1,2,4-triazole as potent inhibitors of antiapoptotic protein Bcl-xL: Synthesis, biological evaluation, and docking studies.

This study describes the synthesis and characterization of a series of novel hydrazide-hydrazone derivatives containing a 1,2,4-triazole ring. The compounds were characterized using various spectroscopic techniques, such as FT-IR, 1H-NMR, 13C-NMR, HRMS, and elemental analysis. The antiproliferative activity of the synthesized compounds was evaluated against a panel of human cancer cell lines (HCT-116, HepG-2, KLN205, LTPA, U138, and SW620) and healthy cell lines (HSkMC and iPSCs). Among the compounds tested, compounds 4, 5p, 5r, and 5s showed the highest effectiveness in inhibiting the growth of cancer cells with Bcl-xL inhibitory concentration (IC50) values. These compounds further demonstrated selective cytotoxicity against the Bcl-xL-dependent lymphoma cell line (DBs). Molecular docking studies were also performed to investigate the potential binding interactions of compounds 4, 5p, 5r, and 5s with the active site of Bcl-xL (PDB ID: 7LH7, 1.4 Å). Mechanistic studies revealed that compounds 4, 5r, and 5s induced apoptosis predominantly through the intrinsic mitochondrial pathway, while compound 5p exhibited a distinct cell cycle arrest profile, impacting both the S and G2/M phases. Western blot analysis suggested that these compounds may downregulate cyclin expression, thereby blocking its association with Bcl-xL. Overall, these results demonstrate the potential of these novel hydrazide-hydrazone derivatives as anticancer agents with activity comparable or superior to doxorubicin and 5-fluorouracil.

Understanding Antimicrobial Peptide Synergy: Differential Binding Interactions and Their Impact on Membrane Integrity.

Research on antimicrobial peptides (AMPs) has been conducted as a solution to overcome antibiotic resistance. In particular, the synergistic effect that appears when two or more AMPs are used in combination has been observed. To find an effective synergistic combination, it is necessary to understand the underlying mechanism. However, a consistent explanation for this phenomenon has not yet been provided due to limitations in experimentally determining or predicting the structure of the heteroaggregates formed by the interactions between different AMPs and the interaction of the aggregate surface with the lipid membrane surface. In this study, we conducted molecular dynamics simulations for two heterogeneous aggregates of melittin-indolicidin and pexiganan-indolicidin to observe their structures in the solution phase and their interactions with the lipid membrane. We aimed to determine how the surfaces of these aggregates interact with the lipid membrane. Due to the different amino acid residue sequence characteristics of melittin and pexiganan, we found that when the two AMPs bind to indolicidin, they form aggregates with completely different structural characteristics. Accordingly, the sequence characteristics of pexiganan, which exhibits a relatively unstable structure compared to melittin in aqueous solution or on lipid membranes, allow for a more stable interaction with the lipid membrane when forming aggregates with indolicidin, effectively inhibiting the integrity of the lipid membranes. We also found that the amino acid residues forming the surface of the AMP aggregate show differential binding strengths to different lipid species forming the lipid membrane, thereby disrupting the membrane in a way that weakens its integrity. Through this, we provided insight into the basic principle of how the synergistic effect of AMPs occurs.

Sulfaquinoxaline-derived Schiff bases: Synthesis, characterization, biological profiling, and computational modeling

Here, six sulfaquinoxaline Schiff bases were synthesized, and various analytical techniques such as FTIR, 1HNMR, and 13CNMR were employed for the characterization. Additionally, in-vitro biological studies were performed, including antibacterial, antifungal, antioxidant, antidiabetic, and anti-inflammatory activities. Computational tools such as molecular docking, DFT, and MD simulations were applied to explore the binding interactions, molecular structure, and chemical reactivity of sulfaquinoxaline SBs. Lastly, in-silico ADMET studies were performed to investigate drug-likeness properties, toxicity, and metabolism of the synthesized SBs. The prepared SBs demonstrated strong antibacterial activity against S. agalactiae and E. coli better than the standard drug, sulfaquinoxaline. The SBs possessed non-significant antioxidant (DPPH assay) and antidiabetic activities (α-amylase and α-glucosidase). All the derivatives depicted moderate anti-inflammatory activity except 6e (IC50 131.95 µg/mL) which presented comparable activity to the standard drug, diclofenac sodium (IC50 127.27 µg/mL). Computational analyses supported the experimental results, especially for compounds 5e and 6e confirming the robust binding affinities and enduring interactions of SBs with the protein target. In-silico drug-likeness analysis and ADMET prediction demonstrated that SBs were drug-like and had a satisfactory ADMET profile.

Selective HLA Class II Allele-Restricted Activation of Atabecestat Metabolite-Specific Human T-Cells.

Elevations in hepatic enzymes were detected in several trial patients exposed to the Alzheimer's drug atabecestat, which resulted in termination of the drug development program. Characterization of hepatic T-lymphocyte infiltrates and diaminothiazine (DIAT) metabolite-responsive, human leukocyte antigen (HLA)-DR-restricted, CD4+ T-lymphocytes in the blood of patients confirmed an immune pathogenesis. Patients with immune-mediated liver injury expressed a restricted panel of HLA-DRB1 alleles including HLA-DRB1*12:01, HLA-DRB1*13:02, and HLA-DRB1*15:01. Thus, the objectives of this study were to (i) generate DIAT-responsive T-cell clones from HLA-genotyped drug-naive donors, (ii) characterize pathways of DIAT-specific T-cell activation, and (iii) assess HLA allele restriction of the DIAT-specific T-cell response. Sixteen drug-naive donors expressing the HLA-DR molecules outlined above were recruited, and T-cell clones were generated. Cellular phenotype, function, and HLA-allele restriction were assessed using culture assays. Peptides displayed by HLA class II molecules in the presence and absence of atabecestat were analyzed by mass spectrometry. Several DIAT-responsive CD4+ clones, displaying no reactivity toward the parent drug, were successfully generated from donors expressing HLA-DRB1*12:01, HLA-DRB1*13:02, and HLA-DRB1*15:01 but not from other donors expressing other HLA-DRB1 alleles. T-cell clones were activated following direct binding of DIAT to HLA-DR proteins expressed on the surface of antigen presenting cells. DIAT binding did not alter the HLA-DRB1 peptide binding repertoire, indicative of a binding interaction with the HLA-associated peptide rather than with the HLA protein itself. DIAT-specific T-cell responses displayed HLA-DRB1*12:01, HLA-DRB1*13:02, and HLA-DRB1*15:01 restriction. These data demonstrate that DIAT displays a degree of selectivity toward HLA protein and associated peptides, with expression of certain alleles increasing and that of others decreasing, the likelihood that a drug-specific T-cell response develops.

Design, Synthesis, Computational Study, and Biological Evaluation of Sulfonyl Tethered Piperazine Derivatives as Antimicrobial Agents

AbstractPiperazine, a nitrogen‐containing heterocyclic compound, has potential in medical chemistry due to its versatile structure and ease of modification. Therefore, researchers have designed novel piperazine derivatives with various biological activities, including antiviral, antibacterial, and antifungal properties. In this study, a new series of 2‐(4‐((5‐bromo‐2‐methoxyphenyl)sulfonyl) piperazine‐1‐yl) acetamide derivatives (7a‐l) were synthesized and their structures were identified using 1H‐NMR, 13C‐NMR, and HRMS spectroscopic methods. The in vitro antimicrobial activity of these compounds was tested against four bacterial strains and two fungi strains. Some of the sulfonyl piperazine derivatives (7d, 7e, 7f, 7j, 7k, and 7l) exhibited relatively good antimicrobial and antifungal activities compared to standard drugs. Further analysis using computational docking confirmed strong binding interactions, aligning with our results. Our compounds exhibited improved potency compared to existing standard treatments.

Exploring multitarget potential of Piper nigrum fruit constituents for Alzheimer's disease: An AI-driven strategy

BackgroundAlzheimer's disease (AD) is a neurodegenerative disease that leads to development of cognition and memory dysfunctions. Currently, there is no known cure for AD, although limited medications are approved for the management of disease condition. Various plant-based leads give new hope for considering phytoconstituents as anti-AD drugs. The Piper nigrum L. fruit extract was reported to have anti-Alzheimer's activity. It creates an interest in the finding of active moieties that may be accountable for anti-AD activity. Hypothesis/PurposeIdentification of multitarget directed ligands isolated from Piper nigrum fruits through AI based studies. Study designThe phytochemical analysis of alkaloid fraction was carried out by LCMS, followed by the evaluation of constituents through in silico studies. MethodsThe fruits methanolic extract was prepared by cold maceration technique. The chemical profiling of the alkaloidal fraction was carried out using LCMS/MS analysis. The obtained compound's target hit genes were identified through network pharmacology studies using String, Metascape, and Cytoscape tools. Further, docking studies and MD simulations were carried out using AutoDock4 and Desmond-Maestro software. Then, electrochemical properties of hit compound P4 were determined using Gaussview6 software. ResultsFrom LCMS/MS analysis data, 29 compounds were considered based on compound intensity and accuracy (>95 %). Then, 41 common gene targets were identified from AD genes and compound-targeted genes. The 41 common genes in the PPI network suggested that AChE and BACE1 were the most abundant proteins. Further, docking studies revealed the hit compound P4 binding interaction and energies when compared to other 28 ligands. The molecular dynamics studies showed that P4-AChE and P4-BACE1 complexes were stable, and there were no RMSD and RMSF fluctuations were observed up to 100 ns. Further, PCA and MM-GBSA analysis data supported that complexes (P4-AChE and P4-BACE1) were stable. The DFT and surface properties indicated that compound P4 was ideal candidate for AD treatment and must be considered for further biological activity studies. ConclusionThe study identified compound P4 (dehydropipernonaline) from alkaloidal fraction of Piper nigrum fruits, suggesting it may be hit candidate for AD treatment.

Integrative bioinformatic and experimental analysis of benzoylbenzodioxol derivatives: hypoglycemic potential in diabetic mice.

We investigated the hypoglycemic activity and pharmacokinetic study of two synthesized benzoyl benzodioxol derivatives, compound I (methyl 2-(6-(2-bromobenzoyl)benzo[d][1,3]dioxol-5-yl)acetate), and compound II, 2-(6-benzoylbenzo[d][1,3]dioxol-5-yl)acetic acid, which showed very strong α-amylase inhibiting activity in our previous study. Then, diabetes was induced by the injection of streptozotocin to mice. The molecular docking simulations and analyses of density functional theory analyses were conducted to study the binding interactions with human pancreatic alpha-amylase, and their pharmacokinetic properties were further evaluated by ADMET profiling. Compound I showed the most important hypoglycemic effect, decreasing the blood glucose by 32.4%, higher than that of compound II by 14.8% and even the positive control acarbose by 22.9%. Histopathological examination revealed that diabetic livers showed portal inflammation with some apoptotic hepatocytes due to streptozotocin treatment, whereas controls without any treatment maintained normal liver architecture. Molecular docking studies gave results for the best binding affinity of the compound I, through its strong water bridges and π-π interactions, and also through analysis with density functional theory, was more stable and reactive when compared to compound II. Further ADMET analysis showed that both compounds shared a promising pharmacokinetic profile, and compound I had the potential for CNS penetration. Thus, compound I was selected as the best candidate for developing new hypoglycemic agents with potent efficacy, good binding interactions, and excellent pharmacokinetic properties.

Ethanol extract of Nymphaea lotus Linn. inhibited hepatic fibrogenesis in carbon tetrachloride-intoxicated Wistar rats

BackgroundNymphaea lotus is a plant used as food and to manage various ailments including liver diseases. Liver fibrosis is a pathological state which progresses to more chronic and fatal liver diseases but without any approved drug yet. This study thus aimed to investigate the anti-liver fibrosis mechanism of N. lotus.MethodologyLiver fibrosis was induced by carbon tetrachloride (CCl4:Olive oil, 1:1 ip). Fibrotic animals were treated with 50, 100 and 200 mg/kg b.wt. N. lotus extract. The activities of alanine aminotransaminase (ALT), aspartate aminotransferase (AST), in the serum, and levels of Malondialdehyde (MDA), superoxide dismutase (SOD), catalase, and reduced glutathione (GSH) in the liver, and histopathology of the liver were determined. The expression of fibrosis-related proteins namely alpha-smooth muscle actin (α-SMA), Collagen-4 (COL4A), Transforming growth factor-β1 (TGFβ1), Mothers against decapentaplegic homolog 2 (SMAD2), SMAD3 and matrix metalloproteinase 2 (MMP2) in the liver was also evaluated. Molecular docking and simulation analysis of N. lotus-derived phytochemicals to TGFβ1 and SMAD3 was also performed.ResultsThe extract significantly reduced the levels of ALT, AST, and MDA, increased the expression of antioxidant enzymes namely; SOD and GSH, and downregulated the expression of fibrosis-related proteins namely α-SMA, COL4A, TGFβ1, SMAD3 and MMP2. It also ameliorated CCl4-induced hepatic lesions. N. lotus-derived phytochemicals also showed a good binding affinity and interaction with the active sites of TGFβ1 and SMAD3.ConclusionN. lotus inhibited liver fibrosis by inhibiting oxidative stress and the TGFβ/SMAD signalling pathway. This demonstrates its beneficial and protective effect against CCl4-induced hepatoxicity and thus supports its use for the traditional management of liver diseases.

Diatomite with gold nanoparticles for atrazine adsorption

Atrazine is a commonly used herbicide worldwide, and it has significant environmental concerns due to its toxic ecological effects. This work uses diatomite decorated with gold nanoparticles to evaluate its capacity for atrazine adsorption. The structural characterization was studied by Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), Energy Dispersive spectroscopy (EDX), Fluorescence microscopy and X-ray photoelectron spectroscopy (XPS). Our findings reveal that diatomite decorated with gold nanoparticles with an average particle size of 10 nm enhances the Raman signal and fluorescence intensity for atrazine detection. Experimental conditions, such as atrazine concentration, pH, contact time, and diatomite mass, have been optimized to quantify the maximum removal conditions using ultraviolet–visible spectroscopy, reaching a maximum adsorption of 2.5 mg/g in 4 h. FTIR and XPS evidence the interaction of the amine groups of the atrazine with the diatomite-decorated surface. The impact of this work relies on environmental remediation using naturally available diatomite decorated with gold nanoparticles and understanding the binding interactions for the removal of atrazine.

Biochemical Characterization and Inhibitor Discovery for Pf Sir2A - New Tricks for An Old Enzyme.

The Sir2 enzyme from Plasmodium falciparum ( Pf Sir2A) is essential for the antigenic variation of this parasite, and its inhibition is expected to have therapeutic effects for malaria. Selective Pf Sir2A inhibitors are not available yet, partially due to the fact that this enzyme demonstrates extremely weak in vitro deacetylase activity, making the characterization of its inhibitors rather challenging. In the current study, we report the biochemical characterization and inhibitor discovery for this enzyme. Pf Sir2A exhibits greater enzymatic activity in the presence of DNA for both the peptide and histone protein substrates, suggesting that nucleosomes may be the real substrates of this enzyme. Indeed, it demonstrates robust deacetylase activity against nucleosome substrates, stemming primarily from the tight binding interactions with the nucleosome. In addition to DNA/nucleosome, free fatty acids (FFAs) are also identified as endogenous Pf Sir2A regulators. Myristic acid, a biologically relevant FFA, shows differential regulation of the two distinct activities of Pf Sir2A: activates deacetylation, but inhibits defatty-acylation. The structural basis of this differential regulation was further explored. Moreover, synthetic small molecule inhibitors of Pf Sir2A were discovered through the screening of a library of human sirtuin regulators. The mechanism of inhibition of the lead compounds were investigated. Collectively, the mechanistic insights and inhibitors described in this study will facilitate the future development of small molecule Pf Sir2A inhibitors as antimalarial agents.

New Pyrazole/Pyrimidine-Based Scaffolds as Inhibitors of Heat Shock Protein 90 Endowed with Apoptotic Anti-Breast Cancer Activity.

Background/Objectives: Supported by a comparative study between conventional, grinding, and microwave techniques, a mild and versatile method based on the [1 + 3] cycloaddition of 2-((3-nitrophenyl)diazenyl)malononitrile to tether pyrazole and pyrimidine derivatives in good yields was used. Methods: The newly synthesized compounds were analyzed with IR, 13C NMR, 1H NMR, mass, and elemental analysis methods. The products show interesting precursors for their antiproliferative anti-breast cancer activity. Results: Pyrimidine-containing scaffold compounds 9 and 10 were the most active, achieving IC50 = 26.07 and 4.72 µM against the breast cancer MCF-7 cell line, and 10.64 and 7.64 µM against breast cancer MDA-MB231-tested cell lines, respectively. Also, compounds 9 and 10 showed a remarkable inhibitory activity against the Hsp90 protein with IC50 values of 2.44 and 7.30 µM, respectively, in comparison to the reference novobiocin (IC50 = 1.14 µM). Moreover, there were possible apoptosis and cell cycle arrest in the G1 phase for both tested compounds (supported by CD1, caspase-3,8, BAX, and Bcl-2 studies). Also, the binding interactions of compound 9 were confirmed through molecular docking, and simulation studies displayed a complete overlay into the Hsp90 protein pocket. Conclusions: Compounds 9 and 10 may have apoptotic antiproliferative action as Hsp90 inhibitors.

Investigating Anion Effects on Metal Ion Binding Interactions With Amyloid β Peptide by Ion Mobility Mass Spectrometry.

The study of metal ion's role in the biological processes of Alzheimer's disease has spurred investigations into the coordination chemistry of amyloid beta peptide and its fragments. Nano-electrospray ionization mass spectrometry (nESI-MS) has been utilized to examine the stabilization of bound anions on multiprotein complexes without bulk solvent. However, the effects of anions on metal ion binding interactions with amyloid beta peptide have not been explored. This study directly examined metal-peptide complexes using nESI-MS and investigated the effects of various anions on the binding ratio and stability of these complexes from ammonium salt solutions. The results indicate that different anions have distinct effects on the binding ratio and stability of various metal-peptide complexes. Of these, the bicarbonate ion exhibits the highest binding ratios for metal-peptide complexes, while binding ratios for these complexes in phosphate are comparatively low. Our results suggest that acetate, formate, bicarbonate, and phosphate have weak affinities and act as weak stabilizers of the metal-peptide complex structure in the gas phase. Intriguingly, chloride and sulfate act as stabilizers of the metal-peptide complex in the gas phase. The rank order determined from these data is substantially different from the Hofmeister salt series in solution. Although this outcome was anticipated due to the reduced influence of anions and water solvation, our findings correlate well with expected anion binding in solution and emphasize the importance of both hydration layer and anion-metal-peptide binding effects for Hofmeister-type stabilization in solution. This approach proved useful in examining the interactions between metal ions and amyloid beta peptide, which are relevant to Alzheimer's disease, using direct ESI-MS.

Synthesis and characterizations of a novel trans-Pd(O,N)2 complex with an AZO-dye ligand: Crystal structure, theoretical studies and DNA binding interactions

The transition metal-azo dye complexes have attracted attention in both fundamental and applied research due to their electronic and structural properties, particularly due to their potential to yield new compounds with diverse biological activities and anticancer agents. A novel square planar-trans-Pd(O,N)2 was synthesized with a high yield utilizing a one-pot approach employing (E)-methyl 2-((2-hydroxynaphthalen-1-yl)diazenyl)benzoate as the AZO-dye ligand. In order to analyze their structure and understand their properties. The desired complex was characterized using FT-IR, UV–Vis, NMR, and CHN-EA techniques. Subsequently, theoretical modeling of the complex was performed using MEP/MAC/NPA methodologies. Two methodologies were employed to monitor the coordination process of AZO-ligand with Pd(II): UV–Vis absorption and FT-IR spectrum analysis. The TD-DFT and DFT/IR behaviors were simultaneously assessed to compare the experimental results with theoretical predictions. Furthermore, both SC-XRD and DFT analysis demonstrated that the deprotonated phenolic diazene form of the AZO-ligand attached to the Pd(II) center by utilizing one nitrogen atom of the AZO-ligand and the ionic oxygen of the phenol. The SC-XRD analysis verified the presence of a slightly distorted square-planar geometry around the PdII center in the neutral trans-Pd(O,N)2 complex. All of the oxygen atoms in the complex participated in non-classical C-H….O hydrogen bonding, leading to the formation of novel edge-fused rings R22(24) and R22(12) synthons. These synthons create a 3D-network with a linked parallel matrix. Interestingly, Hirshfeld surface analysis (HSA) stimulation revealed many hot sites on the complex surface, confirming the formation of strong non-classical [C-H....O] interactions. From the observed docking behavior with the DNA, it can be concluded that the trans-Pd(O,N)2 showed superior binding compared to the free AZO-ligand. The results of this work are a contribution to the study of this class of metal complexes and their physicochemical properties and offer promising perspectives for the realization of new works.

Acrylic Acid Modified Poly-ethylene Glycol Microparticles for Affinity-Based release of Insulin-Like Growth Factor-1 in Neural Applications.

Sustained release of bioactive molecules via affinity-based interactions presents a promising approach for controlled delivery of growth factors. Insulin-like growth factor-1 (IGF-1) has gained increased attention due to its ability to promote axonal growth in the central nervous system. In this work, we aimed to evaluate the effect of IGF-1 delivery from polyethylene-glycol diacrylate (PEG-DA) microparticles using affinity-based sustained release on neurons. We developed PEG-DA-based microparticles with varying levels of acrylic acid (AA) as a comonomer to tune their overall charge. The particles were synthesized via precipitation polymerization under UV light, yielding microparticles (MPs) with a relatively low polydispersity index. IGF-1 was incubated with the PEG-DA particles overnight, and formulations with a higher AA content resulted in higher loading efficiency and slower release rates over 4 weeks, suggesting the presence of binding interactions between the positively charged IGF-1 and negatively charged particles containing AA. The released IGF-1 was tested in dorsal root ganglion (DRG) neurite outgrowth assay and found to retain its biological activity for up to two weeks after encapsulation. Furthermore, the trophic effect of IGF-1 was tested with stem cell-derived V2a interneurons and found to have a synergistic effect when combined with neurotrophin-3 (NT3). To assess the potential of a combinatorial approach, IGF-1-releasing MPs were encapsulated within a hyaluronic acid (HA) hydrogel and showed promise as a dual delivery system. Overall, the PEG-DA MPs developed herein deliver bioactive IGF-1 for a period of weeks and hold potential to enable axonal growth of injured neurons via sustained release.

Study on the cross-resistance of Aedes albopictus (Skuse) (Diptera: Culicidae) to deltamethrin and pyriproxyfen

BackgroundInsecticide resistance poses a significant challenge in the implementation of vector-borne disease control strategies. We have assessed the resistance levels of Aedes albopictus to deltamethrin and pyriproxyfen (PPF) in Fujian Province (China) and investigated the correlation between these resistance levels and mutations in the voltage-gated sodium channel (VGSC).MethodsThe WHO bioassay protocol was used to evaluate the resistance coefficient of Ae. albopictus to deltamethrin and PPF, comparing a susceptible population from the Foshan (FS) area with wild populations from the Sanming (SM), Quanzhou (QZ), Zhangzhou (ZZ), Putian (PT) and Fuzhou (FZ) areas in Fujian Province. Genomic DNA was analyzed by PCR and sequencing to detect knockdown resistance (kdr) in the VGSC, specifically at the pyrethroid resistance alleles V1016V, I1532I and F1534F. Molecular docking was also performed to analyze the binding interactions of PPF and its metabolite 4'-OH-PPF to cytochrome P450 (CYP) 2C19, 2C9 and 3A4 and Ae. albopictus methoprene-tolerant receptors (AeMet), respectively.ResultsThe analysis of resistance to deltamethrin and PPF among Ae. albopictus populations from the various regions revealed that except for the sensitive population in FS and the SM population, the remaining four regional populations demonstrated resistance levels ranging from 4.31- to 18.87-fold for deltamethrin and from 2.85– to 3.62-fold for PPF. Specifically, the FZ and PT populations exhibited high resistance to deltamethrin, whereas the ZZ and QZ populations approached moderate resistance levels. Also, the resistance of the FZ, PT and ZZ populations to PPF increased slowly but consistently with the increasing trend of deltamethrin resistance. Genomic analysis identified multiple non-synonymous mutations within the VGSC gene; the F1534S and F1534L mutations showed significant resistance to deltamethrin in Ae. albopictus. Molecular docking results revealed that PPF and its metabolite 4'-OH-PPF bind to the Ae. albopictus AeMet receptor and CYP2C19.ConclusionsThe wild Ae. albopictus populations of Fujian Province showed varying degrees of resistance to deltamethrin and PPF and a trend of cross-resistance to deltamethrin and PPF. Increased vigilance is needed for potential higher levels of cross-resistance, especially in the PT and FZ regions.Graphical

Molecular mechanism of immunotoxicity: Binding interaction between perfluorinated compounds and human immunoglobulin G

Perfluorinated compounds (PFCs) can induce immunotoxicity effect via binding with proteins. Immunoglobulin G (IgG) is a common four chain monomer protein in serum, and plays an important role in long-term body fluid immunity. Whether PFCs can bind with IgG and further induce immunotoxicity is not clear. Herein, fluorescence quenching assay was used to verify the PFCs-IgG binding interactions. The occurrence of fluorescence quenching phenomenon suggested that PFCs could bind to IgG. Linear fitting curves demonstrated that the binding constants (KA) for perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) were 2.51 × 106 L/mol and 1.58 × 105 L/mol, respectively. UV–vis spectral analysis results showed that the PFCs-IgG interactions mainly proceeded via the intercalation binding mode. Fourier transform infrared spectroscopy results revealed that PFCs preferentially bound to the C=O/N-H of IgG structure. Circular dichroism results revealed that PFCs-IgG binding induced the decrease of α-helix. Moreover, hydrogen bonds and van der Waals force dominated PFCs-IgG binding interactions. This binding process was a stable process, and its stability depended on the number of hydrogen bonds formation. This study reveals the mechanism of interaction between PFCs and IgG at the molecular level, providing a theoretical basis for the immunotoxic mechanism of PFCs.

Design, synthesis, characterization and biological evaluation of coumarin bound 1,2,3-triazoles using click chemistry

In an endeavor to invent new antimalarial and antimicrobial agents, a series of coumarin bound 1,4-disubstituted 1,2,3-triazoles was synthesized through Cu(I)-promoted click reaction between coumarin bound terminal alkynes, that is, 4/7-(prop-2-yn-1-yloxy)-2H-chromen-2-one and 2-azido-N-arylpropanamides. The synthesized 1,2,3-triazoles were characterized by FTIR,1H NMR,13C NMR, and HRMS techniques and were assessed for in vitro antimalarial activity against Plasmodium falciparum as well as in vitro antimicrobial activity against four bacterial strains (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Klebsiella pneumoniae) and two fungal strains (Candida albicans, Aspergillus niger). Compound 7o [(N-(4-fluorophenyl)-2-(4-(((2-oxo-2H-chromen-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide)] displayed better activity against P. falciparum while compound 7y [(N-(3-nitrophenyl)-2-(4-(((2-oxo-2H-chromen-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)propanamide)] displayed excellent activity against all the tested bacterial and fungal strains, amongst the synthesized triazoles. Also, the molecular docking studies of the most potent compounds against DNA gyrase (S. aureus) were also performed to have an insight on binding interactions.

Green Synthesis of Boric Acid Modified Bismuth Based Non-Toxic Perovskite Quantum Dots for Highly Sensitive Detection of Oxytetracycline.

In recent years, perovskite quantum dots (PQDs) have successfully attracted widespread attention due to their excellent optical properties. However, the instability and toxicity problems of perovskite quantum dots are the main obstacles limiting their applications. In this work, bismuth-based perovskite quantum dots were synthesized by a ligand-assisted reprecipitation method, based on which a novel boric acid-functionalized bismuth-based non-toxic perovskite quantum dots fluorescent sensor (Cs3Bi2Br9-APBA) that can be stabilized in the ethanol phase was prepared by a boron affinity technique. Based on the covalent binding interaction of Cs3Bi2Br9-APBA with oxytetracycline (OTC), a highly selective and sensitive method for the detection of OTC was developed, which effectively solved the problems of poor stability and toxicity in the application of perovskite quantum dots. Under the optimal conditions, the fluorescence intensity of the synthesized Cs3Bi2Br9-APBA was linear with the concentration range of 0.1 ∼ 18 µM OTC, and the detection limit could reach 0.0802 µM. The fluorescence detection mechanism was explored and analyzed by spectral overlap analysis, suppression efficiency study of observed and corrected fluorescence, and fluorescence lifetime decay curve fitting, the mechanism of OTC detection by Cs3Bi2Br9-APBA was identified as the inner filter effect (IFE). In addition, the sensor successfully realized the quantitative detection of trace OTC in the environment, and our study provides a new idea for the preparation of green perovskite materials with high stability and selectivity.