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The in silico approach is a smart strategy to identify the potential of a compound to be biologically active against a target disease and to design a more efficient drug candidate. In this work, in silico molecular docking simulation of twenty two (22) newly designed 2‐(2‐(aryl)‐4‐oxo‐4,5‐dihydrothiazol‐5‐yl)acetohydrazides against DNA gyrase subunit B (Gyr B) is performed using AutoDock Vina. The majority of the designed molecules were found to have a binding affinity higher than the moxifloxacin standard drug. The top five scaffolds with the highest binding affinity (ranging from −6.5 to −7.0 kcal/mol) were chosen as the lead depending on the better orientation of the pose and H‐bond interactions. The ADME and toxicity profiles of the selected scaffolds were assessed through SwissADME and Pro‐Tox II, providing valuable insights into their potential safety and efficacy. The chosen compounds had excellent pharmacokinetic characteristics, including low toxicity, good oral bio‐availability, and acceptable GI absorption. The results suggest that the title compounds possess significant potential as lead molecules for the development of novel therapeutics against multidrug‐resistant tuberculosis, providing valuable insights for medicinal chemists and pharmaceutical professionals to design and synthesize novel drug candidates with improved efficacy. [ABSTRACT FROM AUTHOR]

Novel Quinoline‐triazole hybrid derivatives (9 a–9 l) were designed and synthesized via click reaction methodology to develop lead compounds with good antibacterial and antifungal potency. Synthetic compounds have been characterized using 1H NMR, 13C NMR, and mass spectrum analysis. In‐vitro antibacterial activity against two gram‐positive and two gram‐negative strains and in‐vitro antifungal activity against three different strains were performed for the synthesized compounds. Compounds 9 a, 9 d, and 9 i exhibited potent inhibition activity against S. aureus ranging from MIC=12.5–50 μg/mL, and compounds 9 a, 9 c, 9 d, 9 e, 9 f, 9 j, and 9 l exhibited potent inhibition activity against C. albicans fungal strains ranging from MFC=250–500 μg/mL. Molecular docking study of C. albicans Sterol 14α‐demethylase (CYP51) protein (PDB ID:5TZ1) and S. aureus tyrosyl‐tRNA synthetase (PDB ID: 1JIJ) was performed to understand the mechanism of action through which these derivatives work. In silico studies of Hybrid 9 d demonstrated strong hydrogen bonding and π–π interactions with Tyr64, Phe233, and Phe228 in line with the co‐crystals SB‐239629 and VT1161 exhibiting favorable interactions that inhibits both bacterial and fungal strains. [ABSTRACT FROM AUTHOR]

Pallab Kar,1,2 Ayodeji O Oriola,2 Adebola O Oyedeji1,2 1African Medicinal Flora and Fauna Research Niche, Walter Sisulu University, Mthatha, 5117, South Africa; 2Department of Chemical and Physical Sciences, Walter Sisulu University, Mthatha, 5117, South AfricaCorrespondence: Pallab Kar; Adebola O Oyedeji, Email pallabkar.bio@gmail.com; aoyedeji@wsu.ac.zaBackground: The Surinam cherry, Eugenia uniflora belongs to the family Myrtaceae, an edible fruit-bearing medicinal plant with various biological properties. Several anticancer studies have been conducted on its essential oils while the non-essential oil compounds including phenolics, flavonoids, and carotenoids have not been fully investigated.Purpose: Therefore, the study evaluated the in silico anticancer potentials of phenolic, flavonoid, and carotenoid compounds of E. uniflora against the MDM2 and Bcl-xL proteins, which are known to promote cancer cell growth and malignancy. The physicochemical parameters, validation, cytotoxicity, and mutagenicity of the polyphenols were determined using the SwissADME, pkCSM, ProTox-II, and vNN-ADMET online servers respectively. Lastly, the promising phytocompounds were validated using molecular dynamics (MD) simulation.Results: An extensive literature search resulted in the compilation of forty-four (44) polyphenols from E. uniflora. Top-rank among the screened polyphenols is galloylastragalin, which exhibited a binding energy score of − 8.7 and − 8.5 kcal/mol with the hydrophobic interactions (Ala93, Val141) and (Leu54, Val93, Ile99), as well as hydrogen bond interactions (Tyr195) and (Gln72) of the proteins Bcl-xL and MDM2 respectively. A complete in silico toxicity assessment revealed that the compounds, galloylastragalin, followed by myricetin, resveratrol, p-Coumaroylquinic acid, and cyanidin-3-O-glucoside, were potentially non-mutagenic, non-carcinogenic, non-cytotoxic, and non-hepatotoxic. During the 120 ns MD simulations, the RMSF analysis of galloylastragalin- MDM2 (complex 1) and galloylastragalin- Bcl-xL (complex 2) showed the fewest fluctuations, indicating the conformational stability of the respective complexes.Conclusion: This study has shown that polyphenol compounds of E. uniflora led by galloylastragalin, are potent inhibitors of the MDM2 and Bcl-xL cancer proteins. Thus, they may be considered as candidate polyphenols for further anticancer studies.Keywords: Eugenia uniflora, anticancer, in silico molecular docking, in silico toxicity, molecular dynamics simulation, polyphenols, galloylastragalin

A new bidentate Schiff base ligand (C16H16Cl2N4), condensation product of ethylene diamine and 4-chloro N-phenyl formamide, and its metal complexes [M(C16H16Cl2N4)2(OAc)2] (where M = Mn(II) and Zn(II)) were synthesized and characterized using various analytical and spectral techniques, including high-resolution mass spectrometry (HRMS), elemental analysis, ultraviolet-visible (UV-vis), Fourier-transform infrared (FTIR) spectroscopy, AAS, molar conductance, 1H NMR, and powder XRD. All the compounds were non-electrolytes and nanocrystalline. The synthesized compounds were assessed for antioxidant potential by DPPH radical scavenging and FRAP assay, with BHT serving as the positive control. Inhibitory concentration at 50% inhibition (IC50) values were calculated and used for comparative analysis. Furthermore, the prepared compounds were screened for antibacterial activity against two Gram-negative bacteria (Staphylococcus aureus and Bacillus subtilis) and two Gram-positive bacteria (Escherichia coli and Salmonella typhi) using disk-diffusion methods, with amikacin employed as the standard reference. The comparison of inhibition zones revealed that the complexes showed better antibacterial activity than the ligand. To gain insights into the molecular interactions underlying the antibacterial activity, the ligand and complexes were analyzed for their binding affinity with S. aureus tyrosyl-tRNA synthetase (PDB ID: 1JIL) and S. typhi cell membrane protein OmpF complex (PDB ID: 4KR4). These analyses revealed robust interactions, validating the observed antibacterial effects against the tested bacterial strains. [ABSTRACT FROM AUTHOR]

This study focuses on synthesizing a new series of isoxazolinyl-1,2,3-triazolyl-[1,4]-benzoxazin3-one derivatives 5a–5o. The synthesis method involves a double 1,3-dipolar cycloaddition reaction following a “click chemistry” approach, starting from the respective [1,4]-benzoxazin-3-ones. Additionally, the study aims to evaluate the antidiabetic potential of these newly synthesized compounds through in silico methods. This synthesis approach allows for the combination of three heterocyclic components: [1,4]-benzoxazin-3-one, 1,2,3-triazole, and isoxazoline, known for their diverse biological activities. The synthesis procedure involved a two-step process. Firstly, a 1,3-dipolar cycloaddition reaction was performed involving the propargylic moiety linked to the [1,4]-benzoxazin-3-one and the allylic azide. Secondly, a second cycloaddition reaction was conducted using the product from the first step, containing the allylic part and an oxime. The synthesized compounds were thoroughly characterized using spectroscopic methods, including 1H NMR, 13C NMR, DEPT-135, and IR. This molecular docking method revealed a promising antidiabetic potential of the synthesized compounds, particularly against two key diabetes-related enzymes: pancreatic α-amylase, with the two synthetic molecules 5a and 5o showing the highest affinity values of 9.2 and 9.1 kcal/mol, respectively, and intestinal α-glucosidase, with the two synthetic molecules 5n and 5e showing the highest affinity values of −9.9 and −9.6 kcal/mol, respectively. Indeed, the synthesized compounds have shown significant potential as antidiabetic agents, as indicated by molecular docking studies against the enzymes α-amylase and α-glucosidase. Additionally, ADME analyses have revealed that all the synthetic compounds examined in our study demonstrate high intestinal absorption, meet Lipinski’s criteria, and fall within the required range for oral bioavailability, indicating their potential suitability for oral drug development. [ABSTRACT FROM AUTHOR]

Diospyros batokana (Ebenaceae) is a valuable medicinal plant that grows in the wild in Zambia. The aqua crude plant extract is valuable in treating oxidative stress and microbes-related diseases. In this study, bioactive metabolites from the leaf of the plant were tentatively identified using ultra-high-pressure liquid chromatography tandem high-resolution mass spectrometry (UHPLC-HRMS). Raw LCMS data were processed using MZmine3.6. Pyrenophorol, N-[1-(diethylamino)-3-morpholin-4-ylpropan-2-yl]-2,2-diphenylacetamide, losartan, and isoarthonin, (2E,4E)-N-[2-(4-hydroxyphenyl)ethyl]dodeca-2,4-dienamide were among the many metabolites identified from the plant studied using LCMS-MZmine 3.6. Furthermore, in silico anti-inflammatory molecular docking was applied to the five (5) metabolites with the aim of predicting the ability of the metabolites to inhibit the COX-2 enzyme. The docking simulation for the five metabolites was executed using the Auto-dock tools. The lowest binding energy of the complexes was visualized using Discovery Studio, 2021 Client l molecular viewer. Pyrenophorol, (N-[1-(diethylamino)-3-morpholin-4-ylpropan-2-yl] −2,2-diphenylacetamide) and losartan were found to provide the lowest binding energy to COX-2 compared to the standard anti-inflammatory drug, diclofenac. Furthermore, binding affinities, inhibition constants, and ligand efficiencies demonstrated that pyrenophorol, N-[1-(diethylamino)-3-morpholin-4-ylpropan-2-yl]-2,2-diphenylacetamide, losartan, isoarthonin and (2E,4E)-N-[2-(4-hydroxyphenyl)ethyl]dodeca-2,4-dienamide could be useful as anti-inflammatory drug candidates supporting the traditional uses of D. batokana. However, the bioavailability radar and physicochemical properties only predict losartan, pyrenophorol, and (2E,4E)-N-[2-(4-hydroxyphenyl)ethyl]dodeca-2,4-dienamide to be bioavailable and suitable drug candidates. In silico and ADMET analysis, shows that the five metabolites could be used as anti-inflammatory drugs comparable to the standard drugs, diclofenac and ibuprofen. However, in vitro and in vivo studies are needed to further support our findings.

Background: Diabetic nephropathy (DN) is one of the major complications of chronic hyperglycaemia affecting normal kidney functioning. The ayurvedic medicine curcumin (CUR) is pharmaceutically accepted for its vast biological effects.Objectives: The Curcuma-derived diferuloylmethane compound CUR, loaded on Poly (lactide-co-glycolic) acid (PLGA) nanoparticles was utilized to combat DN-induced renal apoptosis by selectively targeting and modulating Bcl2.Methods: Upon in silico molecular docking and screening study CUR was selected as the core phytocompound for nanoparticle formulation. PLGA-nano-encapsulated-curcumin (NCUR) were synthesized following standard solvent displacement method. The NCUR were characterized for shape, size and other physico-chemical properties by Atomic Force Microscopy (AFM), Dynamic Light Scattering (DLS) and Fourier-Transform Infrared (FTIR) Spectroscopy studies. For in vivo validation of nephro-protective effects, Mus musculus were pre-treated with CUR at a dose of 50 mg/kg b.w. and NCUR at a dose of 25 mg/kg b.w. (dose 1), 12.5 mg/kg b.w (dose 2) followed by alloxan administration (100 mg/kg b.w) and serum glucose levels, histopathology and immunofluorescence study were conducted.Results: The in silico study revealed a strong affinity of CUR towards Bcl2 (dock score –10.94 Kcal/mol). The synthesized NCUR were of even shape, devoid of cracks and holes with mean size of ~80 nm having –7.53 mV zeta potential. Dose 1 efficiently improved serum glucose levels, tissue-specific expression of Bcl2 and reduced glomerular space and glomerular sclerosis in comparison to hyperglycaemic group.Conclusion: This study essentially validates the potential of NCUR to inhibit DN by reducing blood glucose level and mitigating glomerular apoptosis by selectively promoting Bcl2 protein expression in kidney tissue.

Multidrug-resistant bacterial pathogens, such as E. coli, represent a major human health threat. Due to the critical need to overcome this dilemma, since the drug efflux pump has a vital function in the evolution of antimicrobial resistance in bacteria, we have investigated the potential of Mentha essential oil major constituents (1–19) as antimicrobial agents via their ability to inhibit pathogenic DNA gyrase and, in addition, their potential inhibition of the E. coli AcrB-TolC efflux pump, a potential target to inhibit MDR pathogens. The ligand docking approach was conducted to analyze the binding interactions of Mentha EO constituents with the target receptors. The obtained results proved their antimicrobial activity through the inhibition of DNA gyrase (1kzn) with binding affinity ΔG values between −4.94 and −6.49 kcal/mol. Moreover, Mentha EO constituents demonstrated their activity against MDR E. coli by their ability to inhibit AcrB-TolC (4dx7) with ΔG values ranging between −4.69 and −6.39 kcal/mol. The antimicrobial and MDR activity of Mentha EOs was supported via hydrogen bonding and hydrophobic interactions with the key amino acid residues at the binding site of the active pocket of the targeted receptors. [ABSTRACT FROM AUTHOR]

This research investigates the extraction of biomass-derived reducing sugars from sugarcane bagasse and their dehydration to fatty acids. The fatty acids were esterified to bioactive fatty acid esters using a catalyst. The contents of the active extracts were analyzed by spectroscopic methods (FT-IR, TGA, ED-XRF, and GC-MS). Applying in silico molecular modeling study, the compounds' possible bioactivity was examined. The compounds were explored for their hepatoprotective potential against selected targets: TNFa (PDB ID: 6MKB), TNF receptor (PDB ID: 1XU2), and GSH reductase (PDB ID: 2LV3). From the results of the docking analysis, compound A was identified to have a binding energy of - 6.4 kcal/mol, -5.4 kcal/mol, and -4.8 kcal/mol against the target proteins respectively. Assessed for their drug-likeness and bioavailability, all compounds were found to follow the Lipinski rule of five, Ghose, Veber, Egan, and Muegge criteria. None of the molecules violated more than one of Lipinski's rules of five. In this regard, the compounds showed good drug-likeness and pharmacokinetic scores, suggesting their potential to be highly bioavailable and active oral drugs with low toxicity. Based on the results, it can be concluded that the bioactive compounds can be used as hepatoprotective agents. [ABSTRACT FROM AUTHOR]

A new bidentate Schiff base ligand (C16H16Cl2N4), condensation product of ethylene diamine and 4-chloro N-phenyl formamide, and its metal complexes [M(C16H16Cl2N4)2(OAc)2] (where M = Mn(II) and Zn(II)) were synthesized and characterized using various analytical and spectral techniques, including high-resolution mass spectrometry (HRMS), elemental analysis, ultraviolet–visible (UV–vis), Fourier-transform infrared (FTIR) spectroscopy, AAS, molar conductance, 1H NMR, and powder XRD. All the compounds were non-electrolytes and nanocrystalline. The synthesized compounds were assessed for antioxidant potential by DPPH radical scavenging and FRAP assay, with BHT serving as the positive control. Inhibitory concentration at 50% inhibition (IC50) values were calculated and used for comparative analysis. Furthermore, the prepared compounds were screened for antibacterial activity against two Gram-negative bacteria (Staphylococcus aureus and Bacillus subtilis) and two Gram-positive bacteria (Escherichia coli and Salmonella typhi) using disk-diffusion methods, with amikacin employed as the standard reference. The comparison of inhibition zones revealed that the complexes showed better antibacterial activity than the ligand. To gain insights into the molecular interactions underlying the antibacterial activity, the ligand and complexes were analyzed for their binding affinity with S. aureus tyrosyl–tRNA synthetase (PDB ID: 1JIL) and S. typhi cell membrane protein OmpF complex (PDB ID: 4KR4). These analyses revealed robust interactions, validating the observed antibacterial effects against the tested bacterial strains.

In this study, a novel series of 7‐[2‐(4‐substituted)‐2‐oxoethyl]amino‐4‐methyl‐2H‐1‐benzopyran‐2‐one derivatives (3 a‐f) were synthesized using 7‐amino‐4‐methyl coumarin and p‐substituted phenacyl bromides, and their pharmacological effects were examined. This reaction was carried out with potassium carbonate as a catalyst in dimethylformamide for 24 h at ambient temperature. The structures of synthesized compounds have been characterized by analysis using FTIR, NMR (1H and 13C) and Mass spectroscopic techniques, and their antibacterial, antidiabetic, and anti‐inflammatory properties have been explored. All synthesized compounds have exhibited good antibacterial activity against S. aureus, B. substilis, E. coli, and S. typhi.Compound 3 f shows maximum activity (zone of inhibition) at a 12 g/mL concentration compared to others. Compounds 3 c and 3 f showed excellent α‐amylase activity and had the lowest IC50 values for α‐glucosidase enzyme activities. The least IC50 value (12.42±0.27 g/mL) was demonstrated by the 3 e compound, which exhibited potent anti‐inflammatory activities. in silico Molecular docking studies suggested that compounds 3 f and 3 a interacted effectively with 4DO3: FAAH and 5DI1: MAP4 K4 proteins with good binding energies of −10.3 and −9.5 Kcal/mol, respectively. [ABSTRACT FROM AUTHOR]

Background: Over the past decade, various research studies have proved the interconnection between the inflammatory pathways and diabetes complication in clinical condition. The present study evaluated the anti-inflammatory and antioxidant activity. Further, the sample was tested for its pharmacokinetics properties and the best compounds were docked with the diabetic markers (DPP IV (PDB-ID: IJ2E) and SGLT2 (PDB-ID: 7VSI)). Results: C.verticillata showed a good hydrogen peroxide (78.3 ± 0.34%, IC50 = 287.81 µg/ml) and superoxide scavenging activity (52.7 ± 1.26%, IC50 = 796.15 µg/ml). In addition, the sample was checked for its anti-inflammatory activity with protein denaturation (57.4 ± 0.19%, IC50 = 471.5 µg/ml) and proteinase inhibition assay (68.3 ± 0.48%, IC50 = 213.42 µg/ml). Further, the bioactive compounds detected from HPLC-ESI-MS/MS analyzed sample were checked for its drug likeliness by checking its ADME properties and toxicological parameters. It has been observed that except Loliolide, all the other compounds have followed the physicochemical parameters and proved to exhibit drug likeliness characteristics. The bioactive compounds that follow the Lipinski's rule were taken further for in silico molecular docking analysis with the diabetic protein markers (DPP IV and SGLT2). Docking results revealed that Pyro pheophorbide a with DPP IV and Dihydromonacolin L acid with SGLT2 have recorded a maximum docking score of (− 9.4 kcal/mol) and (− 9.2 kcal/mol), respectively. Conclusion: The observed results suggest that the identified and selected bioactive compounds from C.verticillata can be considered as a potential target molecule for the management of oxidative stress induced diabetic condition. Furthermore, the study also provides an insight on the effectiveness of the compounds on reducing the inflammation as well. [ABSTRACT FROM AUTHOR]

The article discusses the synthesis of 3,3'-(phenylmethanediyl)bis(4-hydroxy-6-methyl-2H-pyran-2-one) derivatives using Bovine Serum Albumin (BSA) as a catalyst. The researchers investigated the substrate scope and various parameters involved in the synthesis. The structure of the synthesized compounds was determined using spectroscopic techniques, and their biological activity was evaluated. The compounds showed effective results against bacterial activity and moderate inhibition against inflammation. Molecular docking studies were also conducted to determine the interaction of the compounds with the COX-2 receptor. The article provides insights into the potential of biocatalysis and the synthesis of pyran derivatives for various applications. [Extracted from the article]

Pseudomonas aeruginosa is an emerging threat for hospitalized and cystic fibrosis patients. Biofilm, a microbial community embedded in extracellular polymeric substance, fortifies bacteria against the immune system. In biofilms, the expression of functional amyloids is linked with highly aggregative, multi-resistant strains, and chronic infections. Serrapeptase (SPT), a protease possessing similar or superior anti-microbial properties with many antibiotics, presents anti-amyloid potential. However, studies on the employment of SPT against Pseudomonas biofilms and Fap amyloid, or the possible mechanisms of action are scarce. Here, SPT inhibited biofilm formation of P. aeruginosa ATCC 27853 on both plastic and glass surfaces, with an IC50 of 11.26 µg/mL and 0.27 µg/mL, respectively. The inhibitory effect of SPT on biofilm was also verified with optical microscopy of crystal violet-stained biofilms and with confocal microscopy. Additionally, SPT caused a dose-dependent decrease of bacterial viability (IC50 of 3.07 µg/mL) as demonstrated by MTT assay. Reduction of bacterial functional amyloids was also demonstrated, employing both fluorescence microscopy with thioflavin T and photometrical determination of Congo-red-positive compounds. Both viability and functional amyloids correlated significantly with biofilm inhibition. Finally, in silico molecular docking studies provided a mechanistic insight into the interaction of SPT with FapC or FapD, proving that both peptides are possible targets of SPT. These results offer new insights into the biofilm formation of P. aeruginosa and potentiate the involvement of SPT in the prevention and eradication of Pseudomonas biofilms. Key points: • Serrapeptase inhibits biofilm formation of P. aeruginosa on plastic and glass. • Biofilm inhibition correlated with reduced viability and functional amyloid levels. • In silico studies indicated that serrapeptase may target FapC and FapD peptides. [ABSTRACT FROM AUTHOR]

Nimbolide, a tetranortriterpenoid (limonoid) compound isolated from the leaves of Azadirachta indica, was screened both in vitro and in silico for its antimicrobial activity against Fusarium oxysporum f. sp. cubense, Macrophomina phaseolina, Pythium aphanidermatum, Xanthomonas oryzae pv. oryzae, and insecticidal activity against Plutella xylostella. Nimbolide exhibited a concentration-dependent, broad spectrum of antimicrobial and insecticidal activity. P. aphanidermatum (82.77%) was more highly inhibited than F. oxysporum f. sp. cubense (64.46%) and M. phaseolina (43.33%). The bacterium X. oryzae pv. oryzae forms an inhibition zone of about 20.20 mm, and P. xylostella showed about 66.66% mortality against nimbolide. The affinity of nimbolide for different protein targets in bacteria, fungi, and insects was validated by in silico approaches. The 3D structure of chosen protein molecules was built by homology modelling in the SWISS-MODEL server, and molecular docking was performed with the SwissDock server. Docking of homology-modelled protein structures shows most of the chosen target proteins have a higher affinity for the furan ring of nimbolide. Additionally, the stability of the best-docked protein–ligand complex was confirmed using molecular dynamic simulation. Thus, the present in vitro and in silico studies confirm the bioactivity of nimbolide and provide a strong basis for the formulation of nimbolide-based biological pesticides. [ABSTRACT FROM AUTHOR]

Abstract Background Despite the effectiveness of glucagon-like peptide-1 agonist (GLP-1A) in the treatment of diabetes, its large molecular weight and high hydrophilicity result in poor cellular permeability, thus limiting its oral bioavailability. To address this, we developed a chimeric GLP-1A that targets transporter-mediated endocytosis to enhance cellular permeability to GLP-1A by utilizing the transporters available in the intestine, particularly the apical sodium-dependent bile acid transporter (ASBT). Methods In silico molecular docking and molecular dynamics simulations were used to investigate the binding interactions of mono-, bis-, and tetra-deoxycholic acid (DOCA) (monoDOCA, bisDOCA, and tetraDOCA) with ASBT. After synthesizing the chimeric GLP-1A-conjugated oligomeric DOCAs (mD-G1A, bD-G1A, and tD-G1A) using a maleimide reaction, in vitro cellular permeability and insulinotropic effects were assessed. Furthermore, in vivo oral absorption in rats and hypoglycemic effect on diabetic db/db mice model were evaluated. Results In silico results showed that tetraDOCA had the lowest interaction energy, indicating high binding affinity to ASBT. Insulinotropic effects of GLP-1A-conjugated oligomeric DOCAs were not different from those of GLP-1A-Cys or exenatide. Moreover, bD-G1A and tD-G1A exhibited improved in vitro Caco-2 cellular permeability and showed higher in vivo bioavailability (7.58% and 8.63%) after oral administration. Regarding hypoglycemic effects on db/db mice, tD-G1A (50 μg/kg) lowered the glucose level more than bD-G1A (50 μg/kg) compared with the control (35.5% vs. 26.4%). Conclusion GLP-1A was conjugated with oligomeric DOCAs, and the resulting chimeric compound showed the potential not only for glucagon-like peptide-1 receptor agonist activity but also for oral delivery. These findings suggest that oligomeric DOCAs can be used as effective carriers for oral delivery of GLP-1A, offering a promising solution for enhancing its oral bioavailability and improving diabetes treatment. Graphical Abstract

This study focuses on synthesizing a new series of isoxazolinyl-1,2,3-triazolyl-[1,4]-benzoxazin-3-one derivatives 5a–5o. The synthesis method involves a double 1,3-dipolar cycloaddition reaction following a “click chemistry” approach, starting from the respective [1,4]-benzoxazin-3-ones. Additionally, the study aims to evaluate the antidiabetic potential of these newly synthesized compounds through in silico methods. This synthesis approach allows for the combination of three heterocyclic components: [1,4]-benzoxazin-3-one, 1,2,3-triazole, and isoxazoline, known for their diverse biological activities. The synthesis procedure involved a two-step process. Firstly, a 1,3-dipolar cycloaddition reaction was performed involving the propargylic moiety linked to the [1,4]-benzoxazin-3-one and the allylic azide. Secondly, a second cycloaddition reaction was conducted using the product from the first step, containing the allylic part and an oxime. The synthesized compounds were thoroughly characterized using spectroscopic methods, including 1H NMR, 13C NMR, DEPT-135, and IR. This molecular docking method revealed a promising antidiabetic potential of the synthesized compounds, particularly against two key diabetes-related enzymes: pancreatic α-amylase, with the two synthetic molecules 5a and 5o showing the highest affinity values of 9.2 and 9.1 kcal/mol, respectively, and intestinal α-glucosidase, with the two synthetic molecules 5n and 5e showing the highest affinity values of −9.9 and −9.6 kcal/mol, respectively. Indeed, the synthesized compounds have shown significant potential as antidiabetic agents, as indicated by molecular docking studies against the enzymes α-amylase and α-glucosidase. Additionally, ADME analyses have revealed that all the synthetic compounds examined in our study demonstrate high intestinal absorption, meet Lipinski’s criteria, and fall within the required range for oral bioavailability, indicating their potential suitability for oral drug development.

A series of new acylhydrazone derivatives were synthesized from the condensation of different substituted salicylaldehydes with 4‐nitrobenzohydrazide at a molar ratio of 1 : 1 in a one‐step reaction. These compounds have been characterized by spectroscopic techniques such as FT‐IR, NMR, ESI‐MS and CHN analysis. All compounds were examined for anticancer activity in three cancer cell lines viz. melanoma (A375), colon (HT‐29) and lung (A549). Compound 3 exhibits good cytotoxicity activity with an IC50 value of 0.38±0.08 μM against A375 and compound 2 exhibits better cytotoxicity 1.34±0.02 μM and 1.48±0.04 μM against HT‐29 and A549, respectively. Similarly, other compounds have also shown significant cytotoxicity activity against three cell lines. The cytocompatibility assay on the normal mouse fibroblast cell line (L929) and the hemolysis assay on human red blood cells were used to confirm the nontoxic activity. DAPI(4′,6‐diamidino‐2‐phenyliindole) staining experiments demonstrated that compounds induced apoptosis in the A375 cell line. Further, in silico molecular docking was performed against three various targets. In silico studies demonstrated that compounds 1(ΔGb=−9.3 kcal/mol), 2 (ΔGb=−8.8 kcal/mol), and compound 3(ΔGb=−9.0 kcal/mol) have a good binding energy score with an active pocket of protein inhibitor kinases. The outcomes of the current study showed that these compounds have anticancer action and might be used to create more potent drugs to treat melanoma, colon, and lung cancers. [ABSTRACT FROM AUTHOR]

The marine ecosystem harbors unique and diverse bioactive compounds that can offer a vast repertoire of molecules with therapeutic properties. In the present study, four different species of red marine seaweeds were analyzed for its phytoconstituents and the potent antioxidant and anti-inflammatory activity of the methanolic extracts were screened and determined. The results revealed that, among the 4 samples, G. corticata, scored a good antioxidant potential by DPPH (67.61 ± 1.23%, IC50 = 577.7 µg) and metal chelation assay (29.40 ± 0.32%, IC50 = 1684 µg). The anti-inflammatory analysis has shown that, H. dialata was found to exhibit maximum inhibition against the albumin denaturation (83.50 ± 0.24%), whereas G. corticata was observed to measure a maximum inhibition in heat-induced hemolysis (60.40 ± 0.46%) and proteinase inhibition assay (83.30 ± 0.18%). An extensive literature survey was carried out for the bioactive compounds in G.corticata; it was examined for drug likeliness by ADME analysis and toxicological parameters. Further, the best selected bioactive compounds were subjected to in silico molecular docking with pro-inflammatory target, cyclooxygenase (COX-2). Hexadecanal and Neophytadiene were reported to obtain the highest binding affinity (−5.3) for COX-2 enzyme. Hence, in silico molecular docking studies had shown that G. corticata was found to possess potential anti-inflammatory activity that can prevent conversion of arachidonic acid to prostaglandins by inhibiting COX-2. In addition, molecular dynamic simulation studies have shown the stability of Hexadecanal-6 COX complex. To conclude, the outcomes of the present study may shed light on the understanding of the usage of bioactive compounds for therapeutic purpose. [ABSTRACT FROM AUTHOR]

Prodigiosin pigment has high medicinal value, so exploring this compound is a top priority. This report presents a prodigiosin bioactive compound isolated from Serratia marcescens JSSCPM1, a new strain. The purification process of this compound involves the application of different chromatographic methods, including UV-visible spectroscopy, high-performance liquid chromatography (HPLC), and liquid chromatography–mass spectrometry (LC/MS). Subsequent analysis was performed using nuclear magnetic resonance (NMR) to achieve a deeper understanding of the compound's structure. Finally, through a comprehensive review of the existing literature, the structural composition of the isolated bioactive compound was found to correspond to that of the well-known compound prodigiosin. The isolated prodigiosin compound was screened for antibacterial activity against both Gram-positive and Gram-negative bacteria. The compound inhibited the growth of Gram-negative bacterial strains compared with Gram-positive bacterial strains. It showed a maximum minimum inhibitory concentration against Escherichia coli NCIM 2065 at a 15.9 ± 0.31 μg/mL concentration. The potential binding capabilities between prodigiosin and the OmpF porin proteins (4GCS, 4GCP, and 4GCQ) were determined using in silico studies, which are generally the primary targets of different antibiotics. Comparative molecular docking analysis indicated that prodigiosin exhibits a good binding affinity toward these selected drug targets. [ABSTRACT FROM AUTHOR]

Multidrug-resistant bacterial pathogens, such as E. coli, represent a major human health threat. Due to the critical need to overcome this dilemma, since the drug efflux pump has a vital function in the evolution of antimicrobial resistance in bacteria, we have investigated the potential of Mentha essential oil major constituents (1–19) as antimicrobial agents via their ability to inhibit pathogenic DNA gyrase and, in addition, their potential inhibition of the E. coli AcrB-TolC efflux pump, a potential target to inhibit MDR pathogens. The ligand docking approach was conducted to analyze the binding interactions of Mentha EO constituents with the target receptors. The obtained results proved their antimicrobial activity through the inhibition of DNA gyrase (1kzn) with binding affinity ΔG values between −4.94 and −6.49 kcal/mol. Moreover, Mentha EO constituents demonstrated their activity against MDR E. coli by their ability to inhibit AcrB-TolC (4dx7) with ΔG values ranging between −4.69 and −6.39 kcal/mol. The antimicrobial and MDR activity of Mentha EOs was supported via hydrogen bonding and hydrophobic interactions with the key amino acid residues at the binding site of the active pocket of the targeted receptors.

Annona squamosa Linn. (Annonaceae) is a perennial plant that possesses anti-diabetic, antioxidant, anti-tumor, analgesic, and antimicrobial activity. The current study was designed to explore the phytochemicals using GC-MS analysis and to evaluate the antimicrobial activity followed by in-silico molecular docking study. The leaf powder of A. squamosa was successively extracted with n-hexane and methanol. The n-hexane fraction was subjected to GC-MS analysis. The extract was evaluated for antimicrobial activity to determine the zone of inhibition by disc diffusion method at concentrations of 12.5, 25, and 50 mg/ml. The minimum inhibitory concentration was performed at 100, 50, 25, 12.5, 6.25, 3.12 and 1.56 mg/ml concentration, against gram-positive bacteria (Staphylococcus aureus ATCC-25923, Staphylococcus aureus ML-267, Staphylococcus aureus ATCC-29737, Staphylococcus aureus ATCC-29157, Bacillus subtilis-6633), and gram-negative organisms (Escherichia coli PBR-332, Escherichia coli JM-109, Klebsiella pneumoniae PB-12) using streptomycin (1 mg/ml) as standard. Insilico docking was carried out with AUTO-DOCK Tool 1.5.6 using Discovery Studio 3.5. The GC-MS study revealed 13 compounds, the major compounds were 16-hentriacontanone (41.95%); [(1R,2S,6S,7S,8S)-8-Isopropyl-1-methyl-3-methylene-tricyclo-[4.4.0.02,7]-decane] (15.91%) and caryophyllene (12.07%). The better zone of inhibition was found at a concentration of 50 mg/mL against all organisms whereas the Minimum Inhibitory Concentration was detected at 6.25 mg/mL. The docking results revealed through Auto-Dock tool, a highest docking score of -5.2 each obtained from both the compounds caryophyllene and [(1R,2S,6S,7S,8S)-8-Isopropyl-1-methyl-3-methylenetricyclo-[4.4.0.02,7]-decane], which was compared to the that of standard trimethoprim as reported previously. The antimicrobial potential of A. squamosa leaf might be attributed to the synergistic influence of bioactive components identified from GC-MS analysis. [ABSTRACT FROM AUTHOR]

A series of 4-[{2′-(2H-tetrazole-5-yl)-[1,1′-biphenyl]-4-yl}methyl)(2-R-2-oxoethyl)amino]benzoic acid derivatives was synthesized. The obtained compounds were screened for their antibacterial, anticancer and anti-TB activities. In addition, in silico molecular docking studies were carried out on targeted enzymes P38 MAP kinase protein. Calculated ADME properties suggested that the synthesized compounds obeyed all five rules with good bioavailability and there might be no any possibility of causing harmful toxicants, therefore these compounds may be used as drugs. [ABSTRACT FROM AUTHOR]

Repeated trauma, inadequate perfusion or oxygenation, excessive inflammation, infection, oxidative stress, and diabetes all contribute to impaired wound healing. In a clinical setting, delay in healing may result in severe complications such as gangrene, leading to extended hospitalization, amputation and even death of the patient. Slow wound healing and limitations of currently available synthetic medication, urges the need for a safe, affordable, patient-friendly, and multi-modal herbal wound care agent. Anacardium occidentale L., commonly known as cashew and locally, Kaju, is reported to possess antidiabetic, antibacterial, antioxidant, anti-inflammatory and antiulcerogenic activities. In this study, we evaluated the wound healing activity of gel containing the extract of A. occidentale leaves in rats using incision, excision and dead space wound models. Increased wound contraction, breaking strength, hydroxyproline and hexosamine content, TGF-β level and decreased level of TNF-α indicated that the developed gel accelerated the wound healing process. Moreover, the docking studies indicated that the aqueous alcoholic extract exerted healing activity by inhibiting GSK3-β through β-catenin dependent Wnt signaling pathway. Thus, it can be concluded that the Anacardium occidentale leaves extract can be a potential wound healing agent by acting on various phases of healing process. [ABSTRACT FROM AUTHOR]

The current study aimed to investigate the phytochemical contents and antioxidant, antimicrobial, and antibiofilm activities of four halophytic plants, namely, Euphorbia chamaesyce, Bassia arabica, Fagonia mollis, and Haloxylon salicornicum, native to central Saudi Arabia. The alcoholic extract of E. chamaesyce was found to be the most potent in various bioactivities-based evaluations and rich in polyphenols and flavonoid secondary metabolites, with 68.0 mg/g and 39.23 mg/g gallic acid and quercetin equivalents, respectively. Among all plants' extracts, the alcoholic extract of E. chamaesyce had the highest DPPH scavenging and metal chelating antioxidant activities at 74.15 Trolox equivalents and 16.28 EDTA equivalents, respectively. The highest antimicrobial activity of E. chamaesyce extract was found to be against Shigella flexneri, with a mean zone of inhibition diameter of 18.1 ± 0.2 mm, whereas the minimum inhibitory concentration, minimum biocidal concentration, minimum biofilm inhibitory concentration, and minimum biofilm eradication concentration values were 12.5, 25, 25, and 50 mg/mL, respectively. The LC-ESI-MS/MS analysis of the E. chamaesyce extract showed the presence of six flavonoids and ten phenolic constituents. The in silico binding of the E. chamaesyce extract's constituents to Staphylococcus aureus tyrosyl-tRNA synthetase enzyme displayed −6.2 to −10.1 kcal/mol binding energy values, suggesting that these constituents can contribute to the antimicrobial properties of the plant extract, making it an essential medicinal ingredient. In conclusion, these results warrant further investigation to standardize the antimicrobial profiles of these plant extracts. [ABSTRACT FROM AUTHOR]

In this study, we explored a fungal strain UIAU-3F identified as Aspergillus fumigatus isolated from soil samples collected from the River Oyun in Kwara State, Nigeria. In order to explore its chemical diversity, the fungal strain UIAU-3F was cultured in three different fermentation media, which resulted in different chemical profiles, evidenced by LC-ESI-MS-based metabolomics and multivariate analysis. The methanolic extract afforded two known compounds, fumitremorgin C (1) and pseurotin D (2). The in vitro antiparasitic assays of 1 against Trypanosoma cruzi and Plasmodium falciparum showed moderate activity with IC50 values of 9.6 µM and 2.3 µM, respectively, while 2 displayed IC50 values > 50 µM. Molecular docking analysis was performed on major protein targets to better understand the potential mechanism of the antitrypanosomal and antiplasmodial activities of the two known compounds. [ABSTRACT FROM AUTHOR]

The whole world is still challenged with COVID-19 pandemic caused by Coronavirus-2 (SARS-CoV-2) which has affected millions of individuals around the globe. Although there are prophylactic vaccines being used, till now, there is ongoing research into discovery of drug candidates for total eradication of all types of coronaviruses. In this context, this study sought to investigate the inhibitory effects of six selected tropical plants against four pathogenic proteins of Coronavirus-2. The medicinal plants used in this study were selected based on their traditional applications in herbal medicine to treat COVID-19 and related symptoms. The biological activities (antioxidant, free radical scavenging, and anti-inflammatory activities) of the extracts of the plants were assessed using different standard procedures. The phytochemicals present in the extracts were identified using GCMS and further screened via in silico molecular docking. The data from this study demonstrated that the phytochemicals of the selected tropical medicinal plants displayed substantial binding affinity to the binding pockets of the four main pathogenic proteins of Coronavirus-2 indicating them as putative inhibitors of Coronavirus-2 and as potential anti-coronavirus drug candidates. The reaction between these phytocompounds and proteins of Coronavirus-2 could alter the pathophysiology of COVID-19, thus mitigating its pathogenic reactions/activities. In conclusion, phytocompounds of these plants exhibited promising binding efficiency with target proteins of SARS-COV-2. Nevertheless, in vitro and in vivo studies are important to potentiate these findings. Other drug techniques or models are vital to elucidate their compatibility and usage as adjuvants in vaccine development against the highly contagious COVID-19 infection. [ABSTRACT FROM AUTHOR]

Ananas comosus [L.] is one of the most appreciated sources of metabolites for nutraceuticals and therapeutics. Traditional use of A. comosus fruit as anti-inflammatory and anti-arthritic agents warrants scientific validation. A. comosus fruit is well-known for its polyphenolic content and antioxidant activity that pose it good candidate in alleviating arthritis. This study aims to investigate the potential of A. comosus fruit as anti-arthritic and anti-inflammatory agent using different approaches in an attempt to reveal the underlying mechanism of action in accordance to its phytoconstituents. Results revealed that total ethanol extract of A. comosus (TEA) has potent in vitro antioxidant, anti-inflammatory and anti-arthritic activities. Also, TEA (500 and 1000 mg/kg) manifested promising in vivo anti-arthritic activity by alleviating paw edema to only 20.2 and 16.4% increase, respectively. High dose of TEA showed significant reduction in inflammatory biomarkers reverting IL- 6 to near normal value (46.93 pg/mL). TEA reversed the induced histopathological damage caused by the adjuvant and inhibit inducible nitric oxide synthase expression. UPLC/QTOF-MS-MS was carried out for metabolite profiling with a total of 53 metabolites identified including hydroxycinnamic acids (HCA), their depsides, glycerides and glycosides derivatives together with hydroxybenzoic acid glycosides, and amino acids. In silico studies displayed inhibitory potential against TNF-α for most of studied HCA derivatives especially dicinnamoyl glycerides and methoxylated HCA. This study is considered the first pharmacological validation of pineapple fruit traditional use. These observed results are attributed to TEA metabolite profile that exhibited favorable pharmacokinetics and drug likeness properties, suggesting their potential as lead drugs. [Display omitted] • First report on the anti-arthritic activity of total ethanol extract of Ananas comosus edible fruit. • A. comosus fruit exhibited strong antioxidant activity, promising COX-1 inhibitory activity. • A. comosus ameliorated arthritis symptoms in a dose-dependent manner manifested by reduction in pro-inflammatory cytokines. • 53 different metabolites were annotated using UPLC/MS, mainly hydroxycinnamic acids derivatives together with amino acids. • A. comosus is considered a functional food rich in vitamins and carotenoids beside prevalence of bioactive metabolites. [ABSTRACT FROM AUTHOR]

Prodigiosin pigment has high medicinal value, so exploring this compound is a top priority. This report presents a prodigiosin bioactive compound isolated from Serratia marcescens JSSCPM1, a new strain. The purification process of this compound involves the application of different chromatographic methods, including UV-visible spectroscopy, high-performance liquid chromatography (HPLC), and liquid chromatography–mass spectrometry (LC/MS). Subsequent analysis was performed using nuclear magnetic resonance (NMR) to achieve a deeper understanding of the compound’s structure. Finally, through a comprehensive review of the existing literature, the structural composition of the isolated bioactive compound was found to correspond to that of the well-known compound prodigiosin. The isolated prodigiosin compound was screened for antibacterial activity against both Gram-positive and Gram-negative bacteria. The compound inhibited the growth of Gram-negative bacterial strains compared with Gram-positive bacterial strains. It showed a maximum minimum inhibitory concentration against Escherichia coli NCIM 2065 at a 15.9 ± 0.31 μg/mL concentration. The potential binding capabilities between prodigiosin and the OmpF porin proteins (4GCS, 4GCP, and 4GCQ) were determined using in silico studies, which are generally the primary targets of different antibiotics. Comparative molecular docking analysis indicated that prodigiosin exhibits a good binding affinity toward these selected drug targets.

Background: The extensive research in the field of aquaculture is essential to combat the fish bacterial diseases causing massive economic loss to the aquaculture industry and these pathogens remains to be a threat to human well-being due to consumption of fish and fish products as a major food source. Methods: This study focuses on extraction and identification of the antibacterial compound produced by Streptomyces sp. VITNK9 against selected fish bacterial pathogens. Results: Bioactivity-guided extraction of ethyl acetate extract and purification results in isolation of the lead compound 1-(2-hydroperoxycyclopentyl)-4-hydroxytridecan-7-one (HCHD) from Streptomyces sp. VITNK9 having a chemical formula of C18H34O4 and a molecular weight of 314.46 g/mol. HCHD (100 μg/ml) demonstrated antibacterial activity with the inhibition zone of 19.33 ± 0.47 mm and the MIC (minimal inhibitory concentration) of 3.125 μg/ml toward Edwardsiella tarda and 16.66 ± 0.47 mm and the MIC value of 12.5 μg/ml against Aeromonas hydrophila. In silico molecular docking studies showed the interaction of HCHD with the drug target enzyme acetate kinase of E. tarda and A. hydrophila. It showed the least binding free energy of-6.5Kcal/mol and-6.1 Kcal/mol with acetate kinase of E. tarda and A. hydrophila, respectively. Conclusion: The outcome of this study suggests that the inhibition of bacterial acetate kinase by the lead compound HCHD and thereby affects the bacterial metabolism. Streptomyces species are more promising source for isolating antibacterial secondary metabolites for controlling fish bacterial pathogens.

The present study examines the potential activity prediction based on free binding energy (ΔG) and interaction confirmation of phytocompounds from Artocarpus champeden (Lour.) Stokes with macromolecule protein receptor of dipeptidyl peptidase IV (DPP-IV) using in silico molecular docking studies and physicochemical and pharmacokinetic properties (ADME-Tox) prediction approaches. The active subsites of the DPP-IV receptor macromolecule protein Protein Data Bank (ID: 1 × 70) were docked using Autodock v4.2.6 (100 docking runs). A grid box of 52 × 28 × 26 Å points spaced by 0.37 Å was centered on the active site of x = 40.926 Å; y = 50.522 Å; z = 35.031 Å. For ADME-Tox prediction, Swiss ADME online-based application programs were used. The results show that 12 pythocompounds from A. champeden have the potential as DPP-IV inhibitors based on ΔG value and interaction conformation. There are five pythocompounds with lower ΔG values and inhibition constants than the native ligand and seven pythocompounds with ΔG values and inhibition constants close to the native ligand. The 12 compounds form an interaction conformation at the active subsites of the DPP-IV receptor. At the same time, the results of the ADME-Tox prediction analysis showed that the 12 compounds had different physicochemical and pharmacokinetic properties.

Inflammation is a physiological reaction of the immune system required to remove the presence of pathogenic germs. Many herbal-derived extracts and phytoconstituents show anti-inflammatory effects. Among these natural phytoconstituents is Ephedra alte (E. alte), which shows pepsin enzyme inhibitory, antibacterial, and antioxidant activities. In this work, molecular docking study is conducted on five major human anti-inflammatory cytokines receptors (IL-6, hybrid TLR4, TNF-α, IL-1β, and extracted TLR4) to explore the molecular recognition process and complex ligand-receptor interactions of E. alte phytoconstituents. Human TLR4 receptor has been computationally extracted, for the first time, from the hybrid TLR4 human and VLRB inshore hagfish. Among E. alte phytoconstituents, only β-Sitosterol and Androstan-3-one have better LBE (Lowest Binding Energy) scores with inhibition constant (Ki) values than those of other tested compounds. The β-Sitosterol and Androstan-3-one results indicate that these compounds could be efficient inhibitors of inflammation and reduce the oxidative stress by interfering with the activity of the five studied proteins.

[Display omitted] The structure of the lead compound, a natural phaeospha- eride A derivative AV-6, (2 S ,3 R ,4 R)-3-hydroxy-6-methoxy-3-methyl-7-methylene-2-pentyl-4-pyrrolidin-1-yl-3,4,6,7-tetrahydropyrano[2,3- c ]pyrrol-5(2 H)-one, was unambiguously determined by X-ray crystallography. When modeling in silico the interaction of AV-6 with targets in kinase cascades, high values of the binding energy (below –9 kcal mol-1) for some protein targets were shown. Our results identified that MAPK11, MAPK12 and AKT1 could be targets of AV-6. [ABSTRACT FROM AUTHOR]

Introduction: Toll-like receptor 4 (TLR4) has attracted interest due to its role in chemotherapy-induced gastrointestinal inflammation. This structural study aimed to provide in silico rational of the recognition and potential binding of TLR4 ligands IAXO-102, TAK-242, and SN-38 (the toxic metabolite of the chemotherapeutic irinotecan hydrochloride), which could contribute to rationale development of therapeutic anti-inflammation drugs targeting TLR4 in the gastrointestinal tract. Methods: In silico docking was performed between the human TLR4-MD-2 complex and ligands (IAXO-102, TAK-242, SN-38) using Autodock Vina, setting the docking grids to cover either the upper or the lower bound of TLR4. The conformation having the lowest binding energy value (kcal/mol) was processed for post-hoc analysis of the best-fit model. Hydrogen bonding was calculated by using ChimeraX. Results: Binding energies of IAXO-102, TAK-242 and SN-38 at the upper bound of TLR4-MD-2 ranged between − 3.8 and − 3.1, − 6.9 and − 6.3, and − 9.0 and − 7.0, respectively. Binding energies of IAXO-102, TAK-242 and SN-38 at the lower bound ranged between − 3.9 and − 3.5, − 6.5 and − 5.8, and − 8.2 and − 6.8, respectively. Hydrogen bonding at the upper bound of TLR4/MD-2 with IAXO-102, TAK-242 and SN-38 was to aspartic acid 70, cysteine 133 and serine 120, respectively. Hydrogen bonding at the lower bound of TLR4-MD-2 with IAXO-102, TAK-242 and SN-38 was to serine 528, glycine 480 and glutamine 510, respectively. Conclusion: The in silico rational presented here supports further investigation of the binding activity of IAXO-102 and TAK-242 for their potential application in the prevention of gastrointestinal inflammation caused by SN-38. [ABSTRACT FROM AUTHOR]

Simple Summary: Here, we report the eco-friendly synthesis and antitumor potential of the imidazole hybrids of pyrimidine. The results showed that all the compounds possess excellent inhibition of tumors, promoting enzymes hCA-IX and hCA-II. Furthermore, the selectivity index showed that compounds 7, 10, and 11 are selective inhibitors of hCA-IX, while compound 2 is a selective inhibitor of hCA-IX. More importantly, all the active inhibitors are toxic to the breast cancer cell line and non-cytotoxic for the normal breast cell line. These compounds would be a suitable choice to investigate in the in vivo models to check their efficacy against these particular targets. These newly identified human carbonic anhydrase inhibitors have potential to be considered as therapeutic leads for the treatment of CA-related diseases, especially for breast and lung tumors and glaucoma. Furthermore, lead optimization and preclinical and clinical investigations of these compounds are necessary to develop potential drug entities for the treatment of cancer. Imidazole-based pyrimidine hybrids are considered a remarkable class of compounds in pharmaceutical chemistry. Here, we report the anticancer bioactivities of eleven imidazole-based pyrimidine hybrids (1–11) that specifically target cytosolic carbonic anhydrase (CAs) isoenzymes, including human CA-II and human CA-IX (hCA-II, and hCA-IX). A highly eco-friendly aqueous approach was used for the formation of a carbon–carbon bond by reacting aromatic nitro group substitution of nitroimidazoles with carbon nucleophiles. The in vitro results indicate that this new class of compounds (1–11) includes significant inhibitors of hCA IX with IC50 values in the range of 9.6 ± 0.2–32.2 ± 1.0 µM, while hCA II showed IC50 values in range of 11.6 ± 0.2–31.1 ± 1.3 µM. Compound 2 (IC50 = 12.3 ± 0.1 µM) showed selective inhibition for hCA-II while 7, 8, and 10 (IC50 = 9.6–32.2 µM) were selective for hCA-IX. The mechanism of action was investigated through in vitro kinetics studies that revealed that compounds 7, 3, 11, 10, 4, and 9 for CA-IX and 1, 2, and 11 for CA-II are competitive inhibitors with dissociation constant (Ki) in the range of 7.32–17.02 µM. Furthermore, the in situ cytotoxicity of these compounds was investigated in the human breast cancer cell line MDA-MB-231 and compared with the normal human breast cell line, MCF-10A. Compound 5 showed excellent anticancer/cytotoxic activity in MDA-MB-231 with no toxicity to the normal breast cells. In addition, in silico molecular docking was employed to predict the binding mechanism of active compounds with their targets. This in silico observation aligned with our experimental results. Our findings signify that imidazole-based hybrids could be a useful choice to design anticancer agents for breast and lung tumors, or antiglaucoma compounds, by specific inhibition of carbonic anhydrases. [ABSTRACT FROM AUTHOR]

Background: The extensive research in the field of aquaculture is essential to combat the fish bacterial diseases causing massive economic loss to the aquaculture industry and these pathogens remains to be a threat to human well-being due to consumption of fish and fish products as a major food source. Methods: This study focuses on extraction and identification of the antibacterial compound produced by Streptomyces sp. VITNK9 against selected fish bacterial pathogens. Results: Bioactivity-guided extraction of ethyl acetate extract and purification results in isolation of the lead compound 1-(2-hydroperoxycyclopentyl)-4-hydroxytridecan-7-one (HCHD) from Streptomyces sp. VITNK9 having a chemical formula of C18H34O4 and a molecular weight of 314.46 g/mol. HCHD (100 μg/ml) demonstrated antibacterial activity with the inhibition zone of 19.33 ± 0.47 mm and the MIC (minimal inhibitory concentration) of 3.125 μg/ml toward Edwardsiella tarda and 16.66 ± 0.47 mm and the MIC value of 12.5 μg/ml against Aeromonas hydrophila. In silico molecular docking studies showed the interaction of HCHD with the drug target enzyme acetate kinase of E. tarda and A. hydrophila. It showed the least binding free energy of-6.5Kcal/mol and-6.1 Kcal/mol with acetate kinase of E. tarda and A. hydrophila, respectively. Conclusion: The outcome of this study suggests that the inhibition of bacterial acetate kinase by the lead compound HCHD and thereby affects the bacterial metabolism. Streptomyces species are more promising source for isolating antibacterial secondary metabolites for controlling fish bacterial pathogens. [ABSTRACT FROM AUTHOR]

Lysophosphatidylethanolamine (LPE) is a major lysophospholipid produced by phospholipids and binds to human serum albumin (HSA). LPEs may play various roles in vivo depending on the differences in their acyl chains. However, only few reports have been published on the biological functions of LPEs. Hence, we determined the exact relative abundance of the major LPEs in the serum of healthy participants (n = 8) using liquid chromatography–tandem mass spectrometry. Consequently, LPE 18:2 (24.1 ± 5.2%) was found to be the most abundant in serum. To understand the distribution of LPEs, the serum separated via gel‐filtration high‐performance liquid chromatography was subjected to quantitative measurement. LPEs were more observed in the albumin fraction than the lipoprotein fraction. We also performed a fluorescence displacement assay and an in silico molecular docking experiment using AutoDock to confirm the affinity and binding sites of the LPEs on HSA. The binding affinities of the LPEs for drug sites 1 and 2 on HSA were relatively low, with Ki values of approximately 11 and 3.8 μM, respectively. AutoDock analysis revealed the conformation of the LPEs bound to drug sites and the possibility of LPEs binding to other HSA sites. These findings could help to elucidate the biological and pathological functions of LPEs. [ABSTRACT FROM AUTHOR]

Many targeted natural product isolation approaches rely on the use of pre-existing bioactivity information to inform the strategy used for the isolation of new bioactive compounds. Bioactivity information can be available either in the form of prior assay data or via Structure Activity Relationship (SAR) information which can indicate a potential chemotype that exhibits a desired bioactivity. The work described herein utilizes a unique method of targeted isolation using structure-based virtual screening to identify potential antibacterial compounds active against MRSA within the marine sponge order Verongiida. This is coupled with molecular networking-guided, targeted isolation to provide a novel drug discovery procedure. A total of 12 previously reported bromotyrosine-derived alkaloids were isolated from the marine sponge species Pseudoceratina durissima, and the compound, (+)-aeroplysinin-1 (1) displayed activity against the MRSA pathogen (MIC: <32 µg/mL). The compounds (1–3, 6 and 9) were assessed for their central nervous system (CNS) interaction and behavioral toxicity to zebrafish (Danio rerio) larvae, whereby several of the compounds were shown to induce significant hyperactivity. Anthelmintic activity against the parasitic nematode Haemonchus contorutus was also evaluated (2–4, 6–8). [ABSTRACT FROM AUTHOR]

Patent Blue V (PBV) is a water-soluble synthetic dyestuff that is used as a coloring agent in the food industry and for medical imaging in health monitoring. The aim of this study was to investigate the in vitro clastogenic, aneugenic and cytotoxic effects of PBV in human peripheral lymphocytes using micronucleus assay, comet assay, as well as plasmid DNA interaction and bacterial AMES tests. In addition to in vitro tests, the affinity of PBV against DNA was determined by molecular docking analysis in silico. PBV produced significant MN formation only at high doses and longer treatment time, however, it did not significantly affect the nuclear division index (NDI). Furthermore, PBV was unable to cause DNA single-strand breaks and significant oxidative damage on the pBR322 plasmid DNA and it didn't reverse the harmful effects caused by the clastogenic treatment of UV + H2O2 on plasmid DNA. In the Ames test, no significant increase was detected in the number of revertant colonies of mutant strains, TA98 and TA100, following PBV treatment. No significant molecular interaction between B-DNA and PBV occured in molecular docking simulations. In conclusion, PBV had no significant genotoxic and cytotoxic effects in this study. However, considering that the information intensity related to the genotoxic effects of PBV in the literature is still insufficient, reports of further studies with different genotoxicity endpoints will be needed to elucidate the exact genotoxic feature. [ABSTRACT FROM AUTHOR]

Five palladium(II) complexes of substituted salicylaldehydes (X-saloH, X = 4-Et2N (for 1), 3,5-diBr (for 2), 3,5-diCl (for 3), 5-F (for 4) or 4-OMe (for 5)) bearing the general formula [Pd(X-salo)2] were synthesized and structurally characterized. The crystal structure of complex [Pd(4-Et2N-salo)2] was determined by single-crystal X-ray crystallography. The complexes can scavenge 1,1-diphenyl-picrylhydrazyl and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radicals and reduce H2O2. They are active against two Gram-positive (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative (Escherichia coli and Xanthomonas campestris) bacterial strains. The complexes interact strongly with calf-thymus DNA via intercalation, as deduced by diverse techniques and via the determination of their binding constants. Complexes interact reversibly with bovine and human serum albumin. Complementary insights into their possible mechanisms of bioactivity at the molecular level were provided by molecular docking calculations, exploring in silico their ability to bind to calf-thymus DNA, Escherichia coli and Staphylococcus aureus DNA-gyrase, 5-lipoxygenase, and membrane transport lipid protein 5-lipoxygenase-activating protein, contributing to the understanding of the role complexes 1–5 can play both as antioxidant and antibacterial agents. Furthermore, in silico predictive tools have been employed to study the chemical reactivity, molecular properties and drug-likeness of the complexes, and also the drug-induced changes of gene expression profile (as protein- and mRNA-based prediction results), the sites of metabolism, the substrate/metabolite specificity, the cytotoxicity for cancer and non-cancer cell lines, the acute rat toxicity, the rodent organ-specific carcinogenicity, the anti-target interaction profiles, the environmental ecotoxicity, and finally the activity spectra profile of the compounds. [ABSTRACT FROM AUTHOR]

Background: While Molnupiravir and Paxlovid have recently been approved for use in some countries, there are no widely available treatments for COVID-19, the disease caused by SARS-CoV-2 infection. Herbal extracts have been used to treat respiratory clinical indications by Ayurvedic medicine practitioners with minimal adverse reactions and intense research efforts are currently under way to develop some of these formulations for COVID-19 treatment.Methods: Literature search for in silico, in vitro, in vivo, and clinical studies on the topic of Ayurvedic formulations for potential COVID-19 treatment, in order to present the current state of current knowledge by integrating information across all systems.Results: The search yielded 20 peer reviewed articles on in silico studies examining the interaction of phytoconstituents of popular Ayurvedic formulations with SARS-CoV-2 components and its receptors; five articles on preclinical investigations of the ability of selected Ayurvedic formulations to inhibit functions of SARS-CoV-2 proteins; and 51 completed clinical trials on the efficacy of using Ayurvedic formulations for treatment of mild to moderate COVID-19. Clinical data was available from 17 of the 51 trials. There was a considerable overlap between formulations used in the in silico studies and the clinical trials. This finding was unexpected as there is no clearly stated alignment between studies and the traditional pathway to drug discovery– basic discovery leading to in vitro and in vivo proof of concept, followed by validation in clinical trials. This was further demonstrated in the majority of the in silico studies where focus was on potential antiviral mechanisms, while the clinical trials were focused on patient recovery using oral treatments. In all 17 clinical trials where data was available, Ayurvedic treatments lead to a shorter period to recovery in participants with COVID-19.Conclusion: The most commonly used Ayurvedic treatments for management of respiratory symptoms associated with SARS-CoV-2 infection appear to have prophylactic and/or therapeutic properties. It would be of particular interest to assess synergistic and concomitant systemic effects and antiviral activities of individual phytoconstituents and their combinations in the Ayurvedic treatments.

Phytochemical investigations of the twig and leaf extracts of Uvaria dac Pierre ex Finet & Gagnep. resulted in the isolation and identification of five new highly oxygenated cyclohexenes, uvaridacols M − Q (1 – 3 , 5 , and 6), and six known compounds (4 and 7 – 11). All new structures were elucidated by spectroscopic methods and HRESITOFMS data. The absolute configuration of 1 , 5 , and 6 was confirmed by single X-ray diffraction analysis with Cu Kα radiation. In contrast, other compounds were established by comparing their specific rotation and ECD spectra with those of known compounds. Some of the isolated compounds with sufficient quantity were evaluated for their α-glucosidase inhibitory activity. Of these, (−)-1,6-desoxypipoxide (10) showed α-glucosidase inhibitory activity with an IC 50 value of 28.6 μM. The in silico molecular docking of active compounds was also studied. Phytochemical investigations of the twig and leaf extracts of Uvaria dac Pierre ex Finet & Gagnep. resulted in the isolation and identification of five new highly oxygenated cyclohexenes and six known compounds. Some of the isolated compounds with sufficient quantity were evaluated for their α-glucosidase inhibitory activity. Of these, (−)-1,6-desoxypipoxide (10) showed α-glucosidase inhibitory activities with an IC 50 value of 28.6 μM. [Display omitted] • Five new oxygenated cyclohexenes were isolated from Uvaria dac. • The absolute configuration of uvaridacol M, P, Q were confirmed by single X-ray diffraction analysis with Cu Kα radiation. • Oxygenated cyclohexenes containing a cinnamoyl moiety, such as uvaridacols N and P first reported here. • 1,6-Desoxypipoxide showed α -glucosidase inhibitory activity. • 1,6-Desoxypipoxide was docked into α -glucosidase (PDB ID: 2QMJ) in silico molecular docking. [ABSTRACT FROM AUTHOR]

This study examined the efficacy of curcumin (Cur) against lead (Pb)-induced oxidative damage, inflammation, and cholinergic dysfunction. Institute for Cancer Research (ICR) mice received Pb (II) acetate in drinking water (1%) with or without Cur via oral gavage. Blood and brain tissues were collected for investigation. Pb increased the inflammatory markers and oxidative parameters, which were ameliorated by Cur administration. Cur treatment also improved memory loss, learning deficit, and cholinergic dysfunction via elevating acetylcholinesterase (AChE) enzymatic activity and protein expression. In silico molecular docking supported the results; Cur had a potent binding affinity for AChE receptors, tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), phosphorylations of IκB kinase (IKK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38). According to the chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile, Cur could serve as a potential candidate for Pb detoxication substance via exerting antioxidant activity. Taken together, our results suggest that Cur is a natural compound that could be used for the treatment of neurodegenerative disorders via suppressing lead-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

Targeting the apoptosis-inducing pathway has drawn much attention in searching for a novel anticancer drug. Bcl-2 is the most studied antiapoptotic protein, recognised in aiding in cell survival and overexpressed in most cancer cells resulting in cancer resistance toward conventional treatment. The inhibition of Bcl-2 proteins become the main target for inducing apoptosis in cancer cells. β-mangostin received minimum attention in investigating anticancer properties as compared to its family such αmangostin. We performed molecular docking of β-mangostin, doxorubicin (in silico control) and ABT-737 (co-crystal Bcl-2 inhibitor) against antiapoptotic Bcl-2 protein using PyMol, Discovery Studio Biovia 2021, AutoDock Vina, and AutoDock Tools version 1.5.7. The result demonstrates for the first time that β-mangostin showed an optimum binding affinity with Bcl-2 (∆G −7.3 kcal/mol), similar to those shown by doxorubicin. The present results indicate that β-mangostin could potentially serve as Bcl-2 protein inhibitors, which would consequently lead to an apoptotic process in oral cancers. The present data warrant validation using in vitro and in vivo assays. [ABSTRACT FROM AUTHOR]