1,3-Dipolar cycloaddition reactions of a sugar-based trifluoromethylated nitrone-to-maleimide and allyl bromide afforded a series of cycloadducts in good yield. The same nitrone reacts with propargyl ...acetate lead, after rearrangement of 4-isoxazoline, to aziridine with good yield. The obtained compounds were evaluated for their in vitro antimicrobial potency. Additionally, we are interested in predicting their physicochemical parameters such as lipophilicity and bioactivity score as well as their pharmacokinetic properties such as absorption, distribution, metabolism, and excretion (ADME) such as plasma protein binding (PPB) penetration of the blood–brain barrier (BBB), human intestinal absorption (HIA), cellular permeability (PCaco-2), cell permeability of Madin–Darby canine kidney (PMDCK),
P
-glycoprotein (
P
-gp) efflux, CYP inducers, substrates and inhibitors’ skin and permeability (PS), and their toxicological behavior mutagenicity, carcinogenicity, acute, environmental, cardiotoxicity (hERG inhibition) using in silico computational methods. Also, we aimed to validate QSAR models for the elucidation of their antitarget using 32 sets of end-points (
IC
50
,
K
i
and
K
act
). The obtained result provides good information about the pharmacotherapy potential and toxicity of the examined molecules with good compliance between in vitro antimicrobial and the predicted properties. Findings indicated and encouraged the use of these compounds and their derivatives for further in vivo evaluations in the design and the elucidation of the intrinsic mechanisms as well as the efficacy of the selected powerful drug.
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A novel series of enantiopure isoxazolidines have been synthesized in good yields and with high stereoselectivity by 1,3-dipolar cycloaddition between a (–)-menthone-derived nitrone ...as a glycine equivalent and various terminal alkenes. The structures and the stereochemistry of the obtained cycloadducts have been determined by spectroscopic methods. Almost all the compounds were predicted to exhibit various degrees of antioxidant and antibacterial potentiality. Finally, the drug likeness and bioactivity were calculated using Molinspiration software. The results indicated that all compounds are in accordance with Lipinski’s rule of five showing good drug likeness and bioactivity score for drug targets with no violations.
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 IC
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 (IC
= 296.6 ± 0.825 µM and 780.4 ± 0.346 µM), respectively. Specifically, in vitro results revealed that compound
achieved the most inhibitory activity with IC
values of 5.59-fold and 8.27-fold, respectively, toward both enzymes, followed by
. Kinetic studies revealed that compound
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
, which afforded good oral bioavailability. Additionally, compound
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
possesses the potential to simultaneously target both enzymes effectively, making it advantageous for the development of antidiabetic medications.
The main objectives of the present study were to investigate anti-
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
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
ATCC 35016 to 37.33 ± 0.58 mm for
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; β-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
PAO1, and violacein production in
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
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
strains.
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 β-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; β-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.
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 an attempt to rationalize the search for new potential anti-inflammatory and anti-infection agents, a new series of 1,4-and 1,5-disubstituted 1,2,3-triazoles linked benzoxazine conjugates have ...been synthesized via “Click Chemistry” reaction, were designed, synthesized and characterized by means of spectral and elemental data. The newly synthesized compounds have been assessed for their antimicrobial, antioxidant and anti-inflammatory potential. Results revealed that all synthesized compounds display superior activities to the standard drug against different bacterial strains especially S. aureus, M. luteus, and P. aeruginosa, with good to moderate activity towards the tested E. coli bacteria, in respect to the commercial antibiotic, tetracycline. Moreover, the antifungal activity was screened against C. albicans and C. krusei yeasts and results demonstrate potent activity as compared to the standard drug, ampicillin. The antioxidant activity was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging assays, whose results indicate that analogues 4a (IC50 1.88 ± 0.07 µM and 2.17 ± 0.02) followed by 4b (IC50 2.19 ± 0.09 µM and 2.38 ± 0.43 µM), 4d (IC50 2.30 ± 0.01 µM and 4.07 ± 0.57 µM), and 4f (2.98 ± 0.02 µM and 3.80 ± 0.01 µM), respectively, exhibited the strongest activity when compared to the standard reference, butylated hydroxytoluene (BHT) (3.52 ± 0.08 µM and 4.64 ± 0.11 µM). In addition, their anti-inflammatory activity was assessed using the xylene-induced ear edema standard technique and the results demonstrated the potency of 4a, 4b and 4d as excellent anti-inflammatory agents. Preliminary structure–activity relationship studies (SARs) provide those biological activities can be modulated by the presence of unsubstituted aromatic ring as well as the position of substituents on the phenyl moiety via electron withdrawing groups (EWGs) or electron donating groups (EDGs) effects. Docking studies on the most promising compounds 4a, 4b, and 4d into the active sites of S. aureus tyrosyl-tRNA synthetase, Candida albicans N-Myristoyltransferase, Human COX-2 enzyme, and Human Peroxiredoxin 5 revealed good binding profiles with the target proteins. The interaction's stability was further assessed using a conventional atomistic 100 ns dynamic simulation study. Hence, our results recommended the rationalized targets 4a, 4b and 4d, to be promising lead candidates for the discovery of novel dual anti-inflammatory and anti-infection agents.
Plant-based antioxidants such as polyphenols have gained significance in primary health care needs, due to their potential and therapeutic use in modern medicine. Thus, the present study aimed to ...evaluate, for the first time, the effect of solvents on extraction yield, polyphenolics, phytoconstituents and antioxidant properties of various extracts (aqueous, methanol, ethyl acetate, dichloromethane, hexane) of Echium humile Desf. (E. humile Desf.) through in vitro and in silico studies. Statistically, among the various solvents, both methanol (443.05 ± 0.50 mg GAE/g extract) and aqueous (440.59 ± 0.50 mg GAE/g extract) extracts displayed equipotent and highest total phenolics content (TPC), while dichloromethane extract had the maximum total flavonoid content (TFC) (151.69 ± 0.60 mg QE/g extract), total flavonol content (TFlC) (97.39 ± 0.19 mg QE/g extract) and total carotenoids content (TCC) (537.85 ± 5.06 mg β-CE/g). Meanwhile, the highest total condensed tannin content (TCTC) was recorded together with hexane (131.50 ± 0.1 mg GAE/g extract) and dichloromethane (125.74 ± 5.72 GAE/g extract) extracts. The results of antioxidant studies revealed that ethyl acetate extract exhibited a potent scavenging effect through 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•) (IC50 = 17.25 ± 1.76 µg/mL) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+) (1433.30 ± 1.78 µg/mL), while dichloromethane extract displayed significant (p < 0.05) ferric ion reducing antioxidant power (FRAP) activity (375.00 ± 0.02 µg/mL) and total antioxidant capacity (TAC) (1999.00 ± 2.05 µg AAE/g). In addition, the quantification of the polyphenolics content of the most active E. humile Desf. extract, ethyl acetate has been assessed by HPLC/MS, leading to the identification of p-coumaric, trans-ferulic acids and cirsiliol as major constituents. Additionally, molecular docking analysis showed that among the selected phytocompounds, naringin (−7.0 kcal/mol) followed by 1,3-di-O-caffeoyquinic acid (−6.6 kcal/mol), rosmarinic acid (−6.6 kcal/mol), rutin (−6.5 kcal/mol) and apigenin-7-O-glucoside (−6.5 kcal/mol) showed the lowest binding potential. Furthermore, ADME and toxicity parameters justify that identified compounds from ethyl acetate extract are safer to replace the synthetic drugs with side effects. The obtained results can provide valuable information on the medical and therapeutic potential use of E. humile Desf. as a potent antioxidant agent to improve immunity.
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-spirocy-clohexane-1,6’-im-idazo1,5-bisoxazol-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.
The current study aimed to evaluate the naturally occurring antimicrobial and antidiabetic potential of various
(
) 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
-coumaric acid, followed by 4,5-di-
-caffeoylquinic acid, trans-ferulic acid and acacetin. Furthermore,
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
,
and
, fungicidal against
and
and have a bacteriostatic/fungicidal effect for the other strains. In addition, the
methanolic extract had the greatest α-glucosidase inhibitory effect (IC
= 0.06 ± 0.29 mg/mL), which is higher than the standard drug, acarbose (IC
= 0.80 ± 1.81 mg/mL) and the aqueous extract (IC
= 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
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
and its secondary metabolites in the treatment of dual diabetes and infections.
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