Synthesis, optical properties, DNA, ß-cyclodextrin interactions, and antioxidant evaluation of novel isoxazolidine derivative (ISoXD2): A multispectral and computational analysis.

ISoXD2 are well explored among versatile and outstanding class of pharmacophores for the preparation and discovery of drugs. Herein, the electronic absorption and emission spectra of ISoXD2 were investigated in three different solvents. The observed transition was attributed to π-π* with charge transfer character. Changes in the excited state and shift of the absorption and emission peaks to longer wavelengths are observed as a result of increasing solvent polarity, due to the interactions between the ISoXD2 molecule and the solvent molecules surrounding it. Changing the solvent confirms its solvatochromic effect. UV-vis and fluorescence analysis revealed that ISoXD2 binds to deoxyribonucleic acid (DNA) by intercalation mode, with a stoichiometric ratio of 1:1.5. Moreover, the fluorescence intensity of DNA bound to ethidium bromide (EB) in the presence of ISoXD2 was investigated. From this analysis, the Stern-Volmer quenching constant (Ksv), quenching rate constant (kq), binding constant (Kb) and binding sites number (n) were found to be 5.654 × 103 M-1, 2.827 × 1011 M-1 s-1, 3.81 × 104 M-1 and 1.225, respectively. The interaction between ISoXD2 and ß-CD was investigated through absorption spectra analysis. Kb for this interaction was determined to be 4.9 × 104 M-1. The free radical-scavenging ability of the prepared ISoXD2, examined by DPPH and ABTS assays have shown a good antioxidant activity. Furthermore, modeling study was conducted to explore their plausible binding mechanism with ISoXD2 and to support the experimental results.

GC-MS/MS Analysis and Wound Repair Potential of Urtica dioica Essential Oil: In silico Modeling and In vivo Study in Rats.

BACKGROUND: The study aimed to assess the antioxidant and wound healing properties of Urtica dioica essential oil (UDEO) through a comprehensive evaluation involving in silico, in vitro, and in vivo analyses. The phytochemistry of UDEO was also investigated to identify trace compounds crucial. METHODS: Various injection methods of the multimode inlet (MMI) in chromatography were investigated to attain lower instrumental detection limits. Subsequently, in silico studies were employed to delve deeper into the potential biological activities of the identified compounds. Standard antioxidative tests, encompassing ABTS•+ and TAC, were performed. In vivo tests centered on wound healing were implemented using rat models. The rats were randomly allocated to four groups: saline solution, vaseline vehicle, cytol centella, and 5% UDEO ointment. Wound healing progress was evaluated through a chromatic study. RESULTS: Gas chromatography combined with triple quadrupole mass spectrometry (GC-MS/MS) analysis revealed the presence of 97 thermolabile compounds in UDEO. Subsequent in silico studies unveiled the potential of identified compounds to inhibit COX-2, TNF-α, and IL-6, suggesting a possible enhancement of anti-inflammatory responses and healing processes. In vitro tests elucidated the notable antioxidant capacity of UDEO, a finding reinforced by wound healing data, revealing a substantial closure rate of 89% following the topical application of UDEO. Notably, fibrinogen and C-reactive protein (CRP) levels were significantly reduced, indicating minimized oxidative stress damage compared to control. Additionally, UDEO exhibited an increase in antioxidant enzyme activities compared to control. CONCLUSION: The study concludes that UDEO possesses significant antioxidant and wound-healing properties, supported by its rich phytochemical composition. The findings suggest its potential application in therapeutic interventions for oxidative stress and inflammatory conditions.

RETRACTED: Alminderej et al. Antimicrobial and Wound Healing Potential of a New Chemotype from Piper cubeba L. Essential Oil and In Silico Study on S. aureus tyrosyl-tRNA Synthetase Protein. Plants 2021, 10, 205.

The journal retracts the article, 'Antimicrobial and Wound Healing Potential of a New Chemotype from Piper cubeba L. Essential Oil and In Silico Study on S. aureus tyrosyl-tRNA Synthetase Protein' [...].

Synthesis, optical properties, DNA, ß-cyclodextrin interaction, hydrogen isotope sensor and computational study of new enantiopure isoxazolidine derivative (ISoXD).

A novel isoxazolidine derivative (ISoXD) dye was successfully synthesized and comprehensively characterized. In this study, we conducted a thorough examination of its various properties, including optical characteristics, interactions with DNA and ß-cyclodextrin (ß-CD), molecular docking, molecular dynamic simulation, and density functional theory (DFT) calculations. Our investigation encompassed a systematic analysis of the absorption and emission spectra of ISoXD in diverse solvents. The observed variations in the spectroscopic data were attributed to the specific solvent's capacity to engage in hydrogen bonding interactions. Remarkably, the most pronounced intensities were observed in glycol, which can establish many hydrogen bonds with ISoXD. Furthermore, our study revealed a significant distinction in the fluorescence behavior of ISoXD when subjected to different solvents, particularly between CHCl3 and CDCl3. Moreover, we explored the fluorescence intensity of the ISoXD complex in the presence of various metals, both in ethanol and water. The ISoXD complex exhibited a substantial increase of fluorescence upon interaction with different metal ions. The utilization of DFT calculations allowed us to propose an intramolecular charge transfer (ICT) mechanism as a plausible explanation for this quenching phenomenon. The interaction of ISoXD with DNA and ß-CD was studied using absorption spectra. The binding constant (K) and the standard Gibbs free energy change (ΔGo) for the interaction between DNA and ß-CD with ISoXD were determined. In docking study, ISoXD exhibited significant docking scores (-6.511) and MM-GBSA binding free energies (-66.27 kcal/mol) within the PARP-1 binding cavity. Its binding pattern closely resembles to the co-crystal ligand veliparib, and during a 100ns MD simulation, ISoXD displayed strong stability and formed robust hydrogen bonds with key amino acids. These findings suggest ISoXD's potential as a PARP-1 inhibitor for further investigation in therapeutic development.

Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches.

In the development of novel antidiabetic agents, a novel series of isoxazolidine-isatin hybrids were designed, synthesized, and evaluated as dual α-amylase and α-glucosidase inhibitors. The precise structures of the synthesized scaffolds were characterized using different spectroscopic techniques and elemental analysis. The obtained results were compared to those of the reference drug, acarbose (IC50 = 296.6 ± 0.825 µM for α-amylase & IC50 = 780.4 ± 0.346 µM for α-glucosidase). Among the title compounds, 5d exhibited impressive α-amylase and α-glucosidase inhibitory activity with IC50 values of 30.39 ± 1.52 µM and 65.1 ± 3.11 µM, respectively, followed by 5h (IC50 = 46.65 ± 2.3 µM; IC50 = 85.16 ± 4.25 µM) and 5f (IC50 = 55.71 ± 2.78 µM; IC50 = 106.77 ± 5.31 µM). Mechanistic studies revealed that the most potent derivative 5d bearing the chloro substituent attached to the oxoindolin-3-ylidene core, and acarbose, are a competitive inhibitors of α-amylase and α-glucosidase, respectively. Structure activity relationship (SAR) was examined to guide further structural optimization of the most appropriate substituent(s). Moreover, drug-likeness qualities and ADMET prediction of the most active analogue, 5d was also performed. Subsequently, 5d was subjected to molecular docking and dynamic simulation during the progression of 120 ns analysis to check the essential ligand-receptor patterns, and to estimate its stability. In silico studies were found in good agreement with the in vitro enzymatic inhibitions results. In conclusion, we demonstrated that most potent compound 5d could be exploited as dual potential inhibitor of α-amylase and α-glucosidase for possible management of diabetes.

In Silico Design, Synthesis, and Evaluation of Novel Enantiopure Isoxazolidines as Promising Dual Inhibitors of α-Amylase and α-Glucosidase.

Isoxazolidine derivatives were designed, synthesized, and characterized using different spectroscopic techniques and elemental analysis and then evaluated for their ability to inhibit both α-amylase and α-glucosidase enzymes to treat diabetes. All synthesized derivatives demonstrated a varying range of activity, with IC50 values ranging from 53.03 ± 0.106 to 232.8 ± 0.517 µM (α-amylase) and from 94.33 ± 0.282 to 258.7 ± 0.521 µM (α-glucosidase), revealing their high potency compared to the reference drug, acarbose (IC50 = 296.6 ± 0.825 µM and 780.4 ± 0.346 µM), respectively. Specifically, in vitro results revealed that compound 5d achieved the most inhibitory activity with IC50 values of 5.59-fold and 8.27-fold, respectively, toward both enzymes, followed by 5b. Kinetic studies revealed that compound 5d inhibits both enzymes in a competitive mode. Based on the structure-activity relationship (SAR) study, it was concluded that various substitution patterns of the substituent(s) influenced the inhibitory activities of both enzymes. The server pkCSM was used to predict the pharmacokinetics and drug-likeness properties for 5d, which afforded good oral bioavailability. Additionally, compound 5d was subjected to molecular docking to gain insights into its binding mode interactions with the target enzymes. Moreover, via molecular dynamics (MD) simulation analysis, it maintained stability throughout 100 ns. This suggests that 5d possesses the potential to simultaneously target both enzymes effectively, making it advantageous for the development of antidiabetic medications.

GC/MS Profiling, Antibacterial, Anti-Quorum Sensing, and Antibiofilm Properties of Anethum graveolens L. Essential Oil: Molecular Docking Study and In-Silico ADME Profiling.

Anethum graveolens L. has been known as an aromatic, medicinal, and culinary herb since ancient times. The main purpose of this study was to determine the chemical composition, antibacterial, antibiofilm, and anti-quorum sensing activities of the essential oil (EO) obtained by hydro-distillation of the aerial parts. Twelve components were identified, representing 92.55% of the analyzed essential oil. Limonene (48.05%), carvone (37.94%), cis-dihydrocarvone (3.5%), and trans-carvone (1.07%) were the main identified constituents. Results showed that the obtained EO was effective against eight bacterial strains at different degrees. Concerning the antibiofilm activity, limonene was more effective against biofilm formation than the essential oil when tested using sub-inhibitory concentrations. The results of anti-swarming activity tested against P. aeruginosa PAO1 revealed that A. graveolens induced more potent inhibitory effects in the swarming behavior of the PAO1 strain when compared to limonene, with a percentage reaching 33.33% at a concentration of 100 µg/mL. The ADME profiling of the identified phytocompounds confirms their important pharmacokinetic and drug-like properties. The in-silico study using molecular docking approaches reveals a high binding score between the identified compounds and known target enzymes involved in antibacterial and anti-quorum sensing (QS) activities. Overall, the obtained results highlight the possible use of A. graveolens EO to prevent food contamination with foodborne pathogenic bacteria.

In Vitro and In Silico Evaluation of Antiproliferative Activity of New Isoxazolidine Derivatives Targeting EGFR: Design, Synthesis, Cell Cycle Analysis, and Apoptotic Inducers.

A series of novel enantiopure isoxazolidine derivatives were synthesized and evaluated for their anticancer activities against three human cancer cell lines such as human breast carcinoma (MCF-7), human lung adenocarcinoma (A-549), and human ovarian carcinoma (SKOV3) by employing MTT assay. The synthesized compounds were characterized by NMR and elemental analysis. Results revealed that all the synthesized compounds displayed significant inhibition towards the tested cell lines. Among them, 2g and 2f, which differ only by the presence of an ester group at the C-3 position and small EDG (methyl) at the C-5 position of the phenyl ring (2g), were the most active derivatives in attenuating the growth of the three cells in a dose-dependent manner. The IC50 for 2g were 17.7 ± 1 µM (MCF-7), 12.1 ± 1.1 µM (A-549), and 13.9 ± 0.7 µM (SKOV3), and for 2f were 9.7 ± 1.3µM (MCF-7), 9.7 ± 0.7µM (A-549), and 6.5 ± 0.9µM (SKOV3), respectively, which were comparable to the standard drug, doxorubicin. The enzymatic inhibition of 2f and 2g against EGFR afforded good inhibitory activity with IC50 of 0.298 ± 0.007 µM and 0.484 ± 0.01 µM, respectively, close to the positive control, Afatinib. Compound 2f arrested the cell cycle in the S phase in MCF-7 and SKOV3 cells, and in the G2/M phase in the A549 cell; however, 2g induced G0/G1 phase cell cycle arrest, and inhibited the progression of the three cancer cells, together with significant apoptotic effects. The docking study of compounds 2f and 2g into EGFR ATP-active site revealed that it fits nicely with good binding affinity. The pharmacokinetic and drug-likeness scores revealed notable lead-like properties. At 100 ns, the dynamic simulation investigation revealed high conformational stability in the EGFR binding cavity.

A Reversible Optical Sensor Film for Mercury Ions Discrimination Based on Isoxazolidine Derivative and Exhibiting pH Sensing.

We developed a new optical sensor for tracing Hg(II) ions. The detection affinity examines within a concentration range of 0-4.0 µM Hg(II). The sensor film is based on Methyl 2-hydroxy-3-(((2S,2'R,3a'S,5R)-2-isopropyl-5,5'-dimethyl-4'-oxotetrahydro-2'H-spiro[cy-clohexane-1,6'-im-idazo[1,5-b]isoxazol]-2'-yl)methyl)-5-methylbenzoate (IXZD). The novel synthesized compound could be utilized as an optical turn-on chemosensor for pH. The emission intensity is highly enhanced for the deprotonated form concerning the protonated form. IXZD probe has a characteristic fluorescence peak at 481 nm under excitation of 351 nm with large Stocks shift of approximately 130 nm. In addition, the binding process of IXZD:Hg(II) presents a 1:1 molar ratio which is proved by the large quench of the 481 nm emission peak of IXZD and the growth of a new emission peak at 399 nm (blue shift). The binding configurations with one Hg(II) cation and its electronic characteristics were investigated by applying the Density Functional Theory (DFT) and the time-dependent DFT (TDDFT) calculations. Density functional theory (DFT) and the time-dependent DFT (TDDFT) theoretical results were provided to examine Hg(II)-IXZD structures and their electronic properties in solution. The developed chemical sensor was offered based on the intramolecular charge transfer (ICT) mechanism. The sensor film has a significantly low limit of detection (LOD) for Hg(II) of 0.025 µM in pH 7.4, with a relative standard deviation RSDr (1%, n = 3). Lastly, the IXZD shows effective binding affinity to mercury ions, and the binding constant Kb was estimated to be 5.80 × 105 M-1. Hence, this developed optical sensor film has a significant efficiency for tracing mercury ions based on IXZD molecule-doped sensor film.

Multifunctional Derivatives of Spiropyrrolidine Tethered Indeno-Quinoxaline Heterocyclic Hybrids as Potent Antimicrobial, Antioxidant and Antidiabetic Agents: Design, Synthesis, In Vitro and In Silico Approaches.

To combat emerging antimicrobial-resistant microbes, there is an urgent need to develop new antimicrobials with better therapeutic profiles. For this, a series of 13 new spiropyrrolidine derivatives were designed, synthesized, characterized and evaluated for their in vitro antimicrobial, antioxidant and antidiabetic potential. Antimicrobial results revealed that the designed compounds displayed good activity against clinical isolated strains, with 5d being the most potent (MIC 3.95 mM against Staphylococcus aureus ATCC 25923) compared to tetracycline (MIC 576.01 mM). The antioxidant activity was assessed by trapping DPPH, ABTS and FRAP assays. The results suggest remarkable antioxidant potential of all synthesized compounds, particularly 5c, exhibiting the strongest activity with IC50 of 3.26 ± 0.32 mM (DPPH), 7.03 ± 0.07 mM (ABTS) and 3.69 ± 0.72 mM (FRAP). Tested for their α-amylase inhibitory effect, the examined analogues display a variable degree of α-amylase activity with IC50 ranging between 0.55 ± 0.38 mM and 2.19 ± 0.23 mM compared to acarbose (IC50 1.19 ± 0.02 mM), with the most active compounds being 5d, followed by 5c and 5j, affording IC50 of 0.55 ± 0.38 mM, 0.92 ± 0.10 mM, and 0.95 ± 0.14 mM, respectively. Preliminary structure-activity relationships revealed the importance of such substituents in enhancing the activity. Furthermore, the ADME screening test was applied to optimize the physicochemical properties and determine their drug-like characteristics. Binding interactions and stability between ligands and active residues of the investigated enzymes were confirmed through molecular docking and dynamic simulation study. These findings provided guidance for further developing leading new spiropyrrolidine scaffolds with improved dual antimicrobial and antidiabetic activities.

In Vitro and In Silico Screening of Anti-Vibrio spp., Antibiofilm, Antioxidant and Anti-Quorum Sensing Activities of Cuminum cyminum L. Volatile Oil.

Cuminum cyminum L. essential oil (cumin EO) was studied for its chemical composition, antioxidant and vibriocidal activities. Inhibition of biofilm formation and secretion of some virulence properties controlled by the quorum sensing system in Chromobacterium violaceum and Pseudomonas aeruginosa strains were also reported. The obtained results showed that cuminaldehyde (44.2%) was the dominant compound followed by ß-pinene (15.1%), γ-terpinene (14.4%), and p-cymene (14.2%). Using the disc diffusion assay, cumin EO (10 mg/disc) was particularly active against all fifteen Vibrio species, and the highest diameter of growth inhibition zone was recorded against Vibrio fluvialis (41.33 ± 1.15 mm), Vibrio parahaemolyticus (39.67 ± 0.58 mm), and Vibrio natrigens (36.67 ± 0.58 mm). At low concentration (MICs value from 0.023-0.046 mg/mL), cumin EO inhibited the growth of all Vibrio strains, and concentrations as low as 1.5 mg/mL were necessary to kill them (MBCs values from 1.5-12 mg/mL). Using four antioxidant assays, cumin EO exhibited a good result as compared to standard molecules (DPPH = 8 ± 0.54 mg/mL; reducing power = 3.5 ± 0.38 mg/mL; ß-carotene = 3.8 ± 0.34 mg/mL; chelating power = 8.4 ± 0.14 mg/mL). More interestingly, at 2x MIC value, cumin EO inhibited the formation of biofilm by Vibrio alginolyticus (9.96 ± 1%), V. parahaemolyticus (15.45 ± 0.7%), Vibrio cholerae (14.9 ± 0.4%), and Vibrio vulnificus (18.14 ± 0.3%). In addition, cumin EO and cuminaldehyde inhibited the production of violacein on Lauria Bertani medium (19 mm and 35 mm, respectively). Meanwhile, 50% of violacein inhibition concentration (VIC50%) was about 2.746 mg/mL for cumin EO and 1.676 mg/mL for cuminaldehyde. Moreover, elastase and protease production and flagellar motility in P. aeruginosa were inhibited at low concentrations of cumin EO and cuminaldehyde. The adopted in-silico approach revealed good ADMET properties as well as a high binding score of the main compounds with target proteins (1JIJ, 2UV0, 1HD2, and 3QP1). Overall, the obtained results highlighted the effectiveness of cumin EO to prevent spoilage with Vibrio species and to interfere with the quorum sensing system in Gram-negative bacteria by inhibiting the flagellar motility, formation of biofilm, and the secretion of some virulence enzymes.

Tripeptides from Allium subhirsitum L. extracts: Pharmacokinetics properties, toxicity prediction and in silico study against SARS-CoV-2 enzymes and pro-inflammatory proteins.

Developing new prophylactic and therapeutic agents with broad-spectrum antiviral activities is urgently needed to combat emerging human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since no available clinically antiviral drugs have been approved to eradicate COVID-19 as of the writing of this report, this study aimed to investigate bioactive short peptides from Allium subhirsutum L. (Hairy garlic) extracts identified through HR-LC/MS analysis that could potentially hinder the multiplication cycle of SARS-CoV-2 via molecular docking study. The obtained promising results showed that the peptides (Asn-Asn-Asn) possess the highest binding affinities of -8.4 kcal/mol against S protein, (His-Phe-Gln) of -9.8 kcal/mol and (Gln-His-Phe) of -9.7 kcal/mol towards hACE2, (Thr-Leu-Trp) of -10.3 kcal/mol and (Gln-Phe-Tyr) of -9.8 kcal/mol against furin. Additionally, the identified peptides show strong interactions with the targeted and pro-inflammatory ranging from -8.1 to -10.5 kcal/mol for NF-κB-inducing kinase (NIK), from -8.2 to -10 kcal/mol for phospholipase A2 (PLA2), from -8.0 to -10.7 kcal/mol for interleukin-1 receptor-associated kinase 4 (IRAK-4), and from -8.6 to -11.6 kcal/mol for the cyclooxygenase 2 (COX2) with Gln-Phe-Tyr model seems to be the most prominent. Results from pharmacophore, drug-likeness and ADMET prediction analyses clearly evidenced the usability of the peptides to be developed as an effective drug, beneficial for COVID-19 treatment.

Repurposing of anisomycin and oleandomycin as a potential anti-(SARS-CoV-2) virus targeting key enzymes using virtual computational approaches.

Despite the accelerated emerging of vaccines, development against the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) drugs discovery is still in demand. Repurposing the existing drugs is an ideal time/cost-effective strategy to tackle the clinical impact of SARS CoV-2. Thereby, the present study is a promising strategy that proposes the repurposing of approved drugs against pivotal proteins that are responsible for the viral propagation of SARS-CoV-2 virus Angiotensin-converting enzyme-2 (ACE2; 2AJF), 3CL-protease: main protease (6LU7), Papain-like protease (6W9C), Receptor Binding Domain of Spike protein (6VW1), Transmembrane protease serine 2 (TMPRSS-2; 5AFW) and Furin (5MIM) by in silico methods. Molecular docking results were analyzed based on the binding energy and active site interactions accomplished with pharmacokinetic analysis. It was observed that both anisomycin and oleandomycin bind to all selected target proteins with good binding energy, achieving the most favorable interactions. Considering the results of binding affinity, pharmacokinetics and toxicity of anisomycin and oleandomycin, it is proposed that they can act as potential drugs against the SARS CoV-2 infection. Further clinical testing of the reported drugs is essential for their use in the treatment of SARS CoV-2 infection.

Phytochemical Profiling, Antimicrobial and α-Glucosidase Inhibitory Potential of Phenolic-Enriched Extracts of the Aerial Parts from Echium humile Desf.: In Vitro Combined with In Silico Approach.

The current study aimed to evaluate the naturally occurring antimicrobial and antidiabetic potential of various Echium humile (E. humile) solvent extracts (hexane, dichloromethane, ethyl acetate, methanol and aqueous). The bioactive compounds were identified using HPLC-MS, revealing the presence of sixteen phytochemical compounds, with the most abundant being p-coumaric acid, followed by 4,5-di-O-caffeoylquinic acid, trans-ferulic acid and acacetin. Furthermore, E. humile extracts showed marked antimicrobial properties against human pathogen strains, with MIC values for the most relevant extracts (methanol and ethyl acetate) ranging from 0.19 to 6.25 mg/mL and 0.39 to 12.50 mg/mL, respectively. Likewise, methanol was found to be bactericidal towards S. aureus, B. cereus and M. luteus, fungicidal against P. catenulatum and F. oxysporum and have a bacteriostatic/fungicidal effect for the other strains. In addition, the E. humile methanolic extract had the greatest α-glucosidase inhibitory effect (IC50 = 0.06 ± 0.29 mg/mL), which is higher than the standard drug, acarbose (IC50 = 0.80 ± 1.81 mg/mL) and the aqueous extract (IC50 = 0.70 ± 0.67 mg/mL). A correlation study between the major phytochemicals and the evaluated activities was investigated. Docking studies evidenced that most of the identified phenolic compounds showed strong interactions into the binding sites of S. aureus tyrosyl-tRNA synthetase and human lysosomal acid-α-glucosidase, confirming their suitable inhibitory effect. In summary, these results may provide rational support to explore the clinical efficacy of E. humile and its secondary metabolites in the treatment of dual diabetes and infections.

GC-MS Profiling, Vibriocidal, Antioxidant, Antibiofilm, and Anti-Quorum Sensing Properties of Carum carvi L. Essential Oil: In Vitro and In Silico Approaches.

The main objectives of the present study were to investigate anti-Vibrio spp., antibiofilms, and anti-quorum-sensing (anti-QS) properties of caraway essential oil in relation to their phytochemical composition. The results obtained show the identification of twelve compounds, with carvone (58.2%) and limonene (38.5%) being the main ones. The obtained essential oil (EO) is particularly active against all Vibrio spp. species, with bacteriostatic action against all tested strains (MBC/MIC ratio ≥ 4) and with inhibition zones with high diameters of growth, ranging from 8.66 ± 0.58 mm for V. furnisii ATCC 35016 to 37.33 ± 0.58 mm for V. alginolyticus ATCC 17749. Caraway essential oil (Carvone/limonene chemotype) exhibits antioxidant activities by using four tests (DPPH = 15 ± 0.23 mg/mL; reducing power = 7.8 ± 0.01 mg/mL; ß-carotene = 3.9 ± 0.025 mg/mL; chelating power = 6.8 ± 0.05 mg/mL). This oil is particularly able to prevent cell-to-cell communication by inhibiting swarming motility, production of elastase and protease in Pseudomonas aeruginosa PAO1, and violacein production in C. violaceum in a concentration-dependent manner. A molecular docking approach shows good interaction of the identified bioactive molecules in caraway EO, with known target enzymes involved in antioxidant, antibacterial, and anti-QS activities having high binding energy. Overall, the obtained results highlight the possible use of caraway essential oil against pathogenic Vibrio species and to attenuate the secretion of virulence-related factors controlled by QS systems in Gram-negative bacteria. Therefore, this oil can be used by food industries to prevent biofilm formation on abiotic surfaces by Vibrio strains.

Mechanochemical Promoted Heterocycles: A Solvent-free Route to Triazole Carbohydrates as Glycogen Phosphorylase Inhibitors.

AIMS: This study aimed to recommend a novel way for the preparation of carbohydrates containing triazole derivatives. BACKGROUND: Triazoles containing derivatives have numerous biological activities. Ball milling is a fast, modest, green process with massive potential. One of the greatest interesting applications of this technique is in the arena of heterocycles. OBJECTIVE: Solvent-free click reactions are facilitated via the activation of copper powder using a ball milling mechanochemical procedure. An optimization study of parameters affecting the reaction rate, such as reaction time, size, and milling ball number, has been conducted. Different substrates have been tested using this adopted procedure considering in all cases, in high yields and purity, the corresponding chiral optically pure five-membered glycoconjugates containing 1,2,3-triazole. METHODS: Three milling balls of 10 mm in diameter were placed in the milling jar (50 mL; stainless steel). 1 mmol of alkyne, 2 mmol of azide, and 1 mmol of Cu powder (63 mg) were added, respectively, in the presented order. Milling was assured for 25 min at 650 rpm deprived of solvent. RESULTS: The cycloaddition results and the deprotection of the cycloadducts were affected by the selection of the protective groups. Cleavage of the acetyl protecting groups provided water-soluble triazoles. The four 1,4-di-substituted 1,2,3-triazoles synthesized via deacetylation were tested against glycogen phosphorylase. The best inhibitor of rabbit muscle glycogen phosphorylase was 2-Amino-3-{2-[1-(3,4,5,6-tetrahydroxytetrahydro- pyran-2-ylmethyl)-1H-[1,2,3]triazol-4-yl]-ethylsulfanyl}-propionic acid b (Ki = 40.8 ± 3.2 µM). This novel procedure affords an eco-friendly reaction profile (catalyst-free) affording high yields and short reaction times. CONCLUSION: In this work, acetyl protective groups were used to the corresponding deprotected watersoluble triazole analogous to recognizing glycogen phosphorylase inhibitors. Triazole 6a was the most effective inhibitor of RMGP b with a Ki value of 40.8 µM.

Phytochemical Profiling of Allium subhirsutum L. Aqueous Extract with Antioxidant, Antimicrobial, Antibiofilm, and Anti-Quorum Sensing Properties: In Vitro and In Silico Studies.

The present study was the first to evaluate the phytochemical composition, antioxidant, antimicrobial, antibiofilm, and anti-quorum sensing potential of Allium subhirsutum L. (hairy garlic) aqueous extract through in vitro and in silico studies. The phytochemical profile revealed the presence of saponins, terpenes, flavonols/flavonones, flavonoids, and fatty acids, particularly with flavonoids (231 ± 0.022 mg QE/g extract), tannins (159 ± 0.006 mg TAE/g extract), and phenols (4 ± 0.004 mg GAE/g extract). Gas chromatography-mass spectrometry (GC-MS) analysis identified 15 bioactive compounds, such as 5-hydroxymethylfurfural (37.04%), methyl methanethiolsulfonate (21.33%), furfural (7.64%), beta-D-glucopyranose, 1,6-anhydro- (6.17%), 1,6-anhydro-beta-D-glucofuranose (3.6%), trisulfide, di-2-propenyl (2.70%), and diallyl disulfide (1.93%). The extract was found to be non-toxic with 50% cytotoxic concentration higher than 30,000 µg/mL. The investigation of the antioxidant activity via DPPH (2, 2-diphenyl-1-picrylhydrazyl) and FRAP (IC50 = 1 µg/mL), ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid); IC50 = 0.698 ± 0.107 µg/mL), and ß-carotene (IC50 = 0.811 ± 0.036 mg/mL) was assessed. Nevertheless, good antimicrobial potential against a diverse panel of microorganisms with bacteriostatic and fungistatic effect was observed. Quorum sensing inhibition effects were also assessed, and the data showed the ability of the extract to inhibit the production of violacein by the mutant C. violaceum strain in concentration-dependent manner. Similarly, the biofilm formation by all tested strains was inhibited at low concentrations. In silico pharmacokinetic and toxicological prediction indicated that, out of the sixteen identified compounds, fourteen showed promising drug ability and could be used as lead compounds for further development and drug design. Hence, these findings support the popular use of hairy garlic as a source of bioactive compounds with potential application for human health.

HPLC-MS Profiling, Antioxidant, Antimicrobial, Antidiabetic, and Cytotoxicity Activities of Arthrocnemum indicum (Willd.) Moq. Extracts.

The purpose of this study was to evaluate for the first time the phytochemical constituents and biological properties of three (ethanol, acetone, and hexane) Arthrocnemum indicum (Willd.) Moq. (A. indicum) extracts. Quantitative analysis revealed the significantly (p < 0.05) dominance of ethanolic extract on total polyphenol (TPC; 303.67 ± 4.16 mg GAE/g DR) and flavonoid (TFC; 55.33 ± 2.52 mg CE/g DR) contents than the other extracts, also displaying high and equipotent condensed tannin (TCTC) contents as the acetone extract. The qualitative HPLC-MS analysis elucidates 19 and 18 compounds in ethanolic and acetonic extracts, respectively, belonging to the phenolics and flavonoids chemical classes. The extracts were also screened for their in vitro antioxidant activities using 1,1-diphenyl-2-picrylhydrazyl, superoxide anion, and ferric ion (Fe3+) reducing antioxidant power (FRAP), demonstrating the potent antioxidant activity of ethanolic extract, due to its stronger scavenging DPPH• (IC50 = 7.17 ± 1.26 µg/mL) which is not significantly (p > 0.05) different from the positive control, BHT (IC50 = 10.70 ± 0.61 µg/mL), however moderate activity through FRAP and superoxide anion radicals have been observed. Four Gram-positive, four Gram-negative bacteria, and four pathogenic fungi were used for the antimicrobial activity. In addition, S. epidermidis, M. luteus, E. faecalis, C. glabrata, C. parapsilosis, C. krusei were found to be the most susceptible strains towards ethanolic extract. Cytotoxicity values against human colon adenocarcinoma cells (HT29) and human epidermoid cancer cells (Hep2), and one continuous cell lineage control (Vero) revealed that the HT29 cancer cell line was the most responsive to A. indicum shoot extract treatment and significantly (p < 0.05) different from the other cancer cells. Moreover, when tested for their antidiabetic inhibitory effect, ethanol extract recorded the highest antidiabetic effect with IC50 = 13.17 ± 1.04 mg/mL, which is 8.4-fold higher than acetone extract. Therefore, the present study provides new findings on the use of A. indicum shoot ethanolic extract to cure many incurable diseases.

Emetine, a potent alkaloid for the treatment of SARS-CoV-2 targeting papain-like protease and non-structural proteins: pharmacokinetics, molecular docking and dynamic studies.

The main objective of this study is to find out the anti-SARS-CoV-2 potential of emetine by using molecular docking and dynamic simulation approaches. Interestingly, molecular docking studies suggest that Emetine showed significant binding affinity toward Nsp15 (-10.8 kcal/mol) followed by Nsp12 (-9.5 kcal/mol), RNA-dependent RNA polymerase, RdRp (-9.5 kcal/mol), Nsp16 (-9.4 kcal/mol), Nsp10 (-9.2 kcal/mol), Papain-like protein (-9.0 kcal/mol), Nsp13 (-9.0 kcal/mol), Nsp14 (-8.9 kcal/mol) and Spike Protein Receptor Domain (-8.8 kcal/mol) and chymotrypsin-like protease, 3CLpro (-8.5 kcal/mol), respectively, which are essential for viral infection and replication. In addition, molecular dynamic simulation (MD) was also performed for 140 ns to explore the stability behavior of the main targets and inhibitor complexes as well as the binding mechanics of the ligand to the target proteins. The obtained MD results followed by absolute binding energy calculation confirm that the binding of emetine at the level of the various receptors is more stable. The complex EmetineNSP15, mechanistically was stabilized as follows: Emetine first binds to the monomer, after, binds to the second inducing the formation of a dimer which in turn leading to the formation of complex that simulation stabilizes it at a value less than 5 Å. Overall, supported by the powerful and good pharmacokinetic data of Emetine, our findings with clinical trials may be helpful to confirm that Emetine could be promoted in the prevention and eradication of COVID-19 by reducing the severity in the infected persons and therefore can open possible new strategies for drug repositioning. Communicated by Ramaswamy H. Sarma.

Tomatidine and Patchouli Alcohol as Inhibitors of SARS-CoV-2 Enzymes (3CLpro, PLpro and NSP15) by Molecular Docking and Molecular Dynamics Simulations.

Considering the current dramatic and fatal situation due to the high spreading of SARS-CoV-2 infection, there is an urgent unmet medical need to identify novel and effective approaches for prevention and treatment of Coronavirus disease (COVID 19) by re-evaluating and repurposing of known drugs. For this, tomatidine and patchouli alcohol have been selected as potential drugs for combating the virus. The hit compounds were subsequently docked into the active site and molecular docking analyses revealed that both drugs can bind the active site of SARS-CoV-2 3CLpro, PLpro, NSP15, COX-2 and PLA2 targets with a number of important binding interactions. To further validate the interactions of promising compound tomatidine, Molecular dynamics study of 100 ns was carried out towards 3CLpro, NSP15 and COX-2. This indicated that the protein-ligand complex was stable throughout the simulation period, and minimal backbone fluctuations have ensued in the system. Post dynamic MM-GBSA analysis of molecular dynamics data showed promising mean binding free energy 47.4633 ± 9.28, 51.8064 ± 8.91 and 54.8918 ± 7.55 kcal/mol, respectively. Likewise, in silico ADMET studies of the selected ligands showed excellent pharmacokinetic properties with good absorption, bioavailability and devoid of toxicity. Therefore, patchouli alcohol and especially, tomatidine may provide prospect treatment options against SARS-CoV-2 infection by potentially inhibiting virus duplication though more research is guaranteed and secured.