In Vitro and In Silico Studies of the Antimicrobial Activity of Prenylated Phenylpropanoids of Green Propolis and Their Derivatives against Oral Bacteria.

Artepillin C, drupanin, and plicatin B are prenylated phenylpropanoids that naturally occur in Brazilian green propolis. In this study, these compounds and eleven of their derivatives were synthesized and evaluated for their in vitro antimicrobial activity against a representative panel of oral bacteria in terms of their minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values. Plicatin B (2) and its hydrogenated derivative 8 (2',3',7,8-tetrahydro-plicatin B) were the most active compounds. Plicatin B (2) displayed strong activity against all the bacteria tested, with an MIC of 31.2 µg/mL against Streptococcus mutans, S. sanguinis, and S. mitis. On the other hand, compound 8 displayed strong activity against S. mutans, S. salivarius, S. sobrinus, Lactobacillus paracasei (MIC = 62.5 µg/mL), and S. mitis (MIC = 31.2 µg/mL), as well as moderate activity against Enterococcus faecalis and S. sanguinis (MIC = 125 µg/mL). Compounds 2 and 8 displayed bactericidal effects (MBC: MIC ≤ 4) against all the tested bacteria. In silico studies showed that the complexes formed by compounds 2 and 8 with the S. mitis, S. sanguinis, and S. mutans targets (3LE0, 4N82, and 3AIC, respectively) had energy score values similar to those of the native S. mitis, S. sanguinis, and S. mutans ligands due to the formation of strong hydrogen bonds. Moreover, all the estimated physicochemical parameters satisfied the drug-likeness criteria without violating the Lipinski, Veber, and Egan rules, so these compounds are not expected to cause problems with oral bioavailability and pharmacokinetics. Compounds 2 and 8 also had suitable ADMET parameters, as the online server pkCSM calculates. These results make compounds 2 and 8 good candidates as antibacterial agents against oral bacteria.

CO2 Capture by Diamines in Dry and Humid Conditions: A Theoretical Approach.

This work is a mechanistic study of the CO2 reaction with diamines under both dry and wet conditions. All protic α,ω-diamines R1H1N1-(CH2)n-N2H2R2, with n = 1-5 and R1 and R2 = H and/or CH3, were investigated. Depending on the nature of the diamine, the reaction was found to follow one of two concerted asynchronous reaction mechanisms with a zwitterion hidden intermediate. Both mechanisms involved two processes. The first process consisted of a nucleophilic attack of the nitrogen N1 of the first amine group on the carbon of CO2, accompanied by the transfer of a hydrogen atom H1 from N1 to the nitrogen N2 of the second amine group, leading to the formation of a carbamate zwitterion. The subsequent process corresponds to the transfer of a hydrogen atom H2 from the second amine group N2 to an oxygen atom of CO2, thus ending the reaction by the formation of carbamic acid. The structure of the zwitterion hidden intermediate was determined using the reactive internal reaction coordinates (RIRC), a reaction pathway visualization tool, consisting of a 3D representation of the potential energy versus the internuclear distances N2-H1 and N2-H2, which correspond to the bond being formed and the bond being broken, respectively. The life span of the transitory species, i.e., the zwitterion, was found to depend on the nature of the second amine group. For primary amines, the life span of the zwitterion was "short", whereas for secondary amines, it was "long". The corresponding mechanisms were termed the "early" and "late" asynchronous mechanism, respectively. Regardless of the mechanism, the activation barriers were found to decrease with the length of the carbon chain linking the two amine groups, with an asymptotic behavior from n = 4. Involvement of a water molecule generates a significant catalytic effect for diamines with short carbon chains (n < 4), whereas for longer chain diamines, water has a slightly adverse effect.

Versatile anti-infective properties of pyrido- and dihydropyrido[2,3-d]pyrimidine-based compounds.

A series of 1H-indeno[2',1':5,6]dihydropyrido[2,3-d]pyrimidine and 1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine derivatives was prepared and screened for antiparasitic and viral RNase H inhibitory activity. Several compounds showed considerable activity against Toxoplasma gondii parasites and Leishmania major amastigotes, which warrants further investigation. Based on the structural similarities of certain derivatives with common viral RNase H inhibitors, a HIV-1 RNase H assay was used to study the RNase H inhibition by selected test compounds. Docking of active derivatives into the active site of the HIV-1 RNase H enzyme was carried out. The new compound 2a, inactive in the antiparasitic tests, showed distinct HIV-1 RNase H inhibition. Thus, ring substitution determines antiparasitic or HIV-1 RNase H inhibitory activity of this promising compound class.

Evaluation of the Antiparasitic and Antifungal Activities of Synthetic Piperlongumine-Type Cinnamide Derivatives: Booster Effect by Halogen Substituents.

A series of synthetic N-acylpyrrolidone and -piperidone derivatives of the natural alkaloid piperlongumine were prepared and tested for their activities against Leishmania major and Toxoplasma gondii parasites. Replacement of one of the aryl meta-methoxy groups by halogens such as chlorine, bromine and iodine led to distinctly increased antiparasitic activities. For instance, the new bromo- and iodo-substituted compounds 3 b/c and 4 b/c showed strong activity against L. major promastigotes (IC50 =4.5-5.8 µM). Their activities against L. major amastigotes were moderate. In addition, the new compounds 3 b, 3 c, and 4 a-c exhibited high activity against T. gondii parasites (IC50 =2.0-3.5 µM) with considerable selectivities when taking their effects on non-malignant Vero cells into account. Notable antitrypanosomal activity against Trypanosoma brucei was also found for 4 b. Antifungal activity against Madurella mycetomatis was observed for compound 4 c at higher doses. Quantitative structure-activity relationship (QSAR) studies were carried out, and docking calculations of test compounds bound to tubulin revealed binding differences between the 2-pyrrolidone and 2-piperidone derivatives. Microtubules-destabilizing effects were observed for 4 b in T. b. brucei cells.

Fingerprinting of two an acylated polyoxypregnane glycosides from Caralluma quadrangula (Forssk.) N.E.Br. using UPLC-ESI-Q-TOF and computational study.

The present study has tentatively elucidated the structure of two acylated polyoxypregnane glycosides from Caralluma quadrangula (Forssk.) N.E.Br. (CQ). The analyses were performed using an electrospray-ionization quadrupole time-of-flight (ESI-Q-TOF) mass spectrometer in positive ionization modes to explore fragmentation pathways. The used ionization mode provided consistent and/or complementary information for most of the pregnane glycosides, their fragmentation sequences, and their aglycones. Presumably, this is due to higher efficiency, sensitivity, and better selectivity of the mass spectrometry-based method. The present experimental and theoretical report deals with the characteristic fragmentation behaviors of two acylated polyoxypregnane glycosides CQ1 and CQ2 from the aerial parts of C. quadrangular. A DFT Study was performed to elucidate the position of ikemoyl, and benzoyl residues in compounds CQ1 and CQ2, respectively.

Removal of Malachite Green Dye from Aqueous Solution by Catalytic Wet Oxidation Technique Using Ni/Kaolin as Catalyst.

In this study, natural Algerian kaolin was used as a support and impregnated with nickel at different loading amounts (2 wt.%, 5 wt.%, and 7 wt.%) in order to prepare a supported catalyst. The wet impregnation technique was used in this preparation; nickel oxide (NiO) was the active phase precursor of the catalyst, and the catalysts were designated as follows: 2%, 5%, and 7% Ni/kaolin. These catalysts were put to the test in catalytic wet peroxide oxidation (CWPO) for degrading the organic contaminant malachite green dye (MG). Analytical techniques such as FTIR spectroscopy, X-ray diffraction, BET, and X-fluorescence were used to examine the structure, morphology, and chemical composition of the support and the produced catalysts. Several parameters, including temperature, catalytic dose, metal loading, hydrogen peroxide volume, and kinetic model were systematically investigated. The combination of improved parameters resulted in a significant increase in the catalytic activity, achieving a high removal rate of MG dye of 98.87%.

Enhanced adsorptive removal of indigo carmine dye by bismuth oxide doped MgO based adsorbents from aqueous solution: equilibrium, kinetic and computational studies.

Novel doped MgO nanoadsorbents were effectively fabricated at various Bi2O3 doping concentrations (0, 2.5, 5 and 10%). DFT-D3 study showed that the doping is done by substitution of two magnesium atoms by two bismuth atoms with the creation of a vacancy of one Mg atom. TEM, SEM, EDX, BET, XRD, and FTIR were used to characterize the obtained nanostructures. The removal of indigo carmine (IC) dyes from wastewater by doped MgO nanoparticles is investigated. Experimental parameters such as the initial dye concentration, contact time, Bi2O3 doping concentration, and pH were optimized to enhance the adsorption capacity. Bi2O3 doped MgO prepared at 5% (MgOBi2) is the best adsorbent with a maximum IC adsorption capacity of 126 mg g-1 at a solution pH equal to 7.00 and contact time of 74 min. The results indicated that the adsorption process followed pseudo-second-order (PSO) reaction kinetics, and the Freundlich isotherm model gave a better goodness-of-fit than the linear Langmuir model. The FTIR study established that IC molecules are successfully adsorbed onto the surface of MgOBi2 via a chemisorption process.

In Search of Preferential Macrocyclic Hosts for Sulfur Mustard Sensing and Recognition: A Computational Investigation through the New Composite Method r2SCAN-3c of the Key Factors Influencing the Host-Guest Interactions.

Sulfur mustard (SM) is a harmful warfare agent that poses a serious threat to human health and the environment. Thus, the design of porous materials capable of sensing and/or capturing SM is of utmost importance. In this paper, the interactions of SM and its derivatives with ethylpillar[5]arene (EtP[5]) and the interactions between SM and a variety of host macrocycles were investigated through molecular docking calculations and non-covalent interaction (NCI) analysis. The electronic quantum parameters were computed to assess the chemical sensing properties of the studied hosts toward SM. It was found that dispersion interactions contributed significantly to the overall complexation energy, leading to the stabilization of the investigated systems. DFT energy computations showed that SM was more efficiently complexed with DCMP[5] than the other hosts studied here. Furthermore, the studied macrocyclic containers could be used as host-based chemical sensors or receptors for SM. These findings could motivate experimenters to design efficient sensing and capturing materials for the detection of SM and its derivatives.

Highly Selective Removal of Cationic Dyes from Wastewater by MgO Nanorods.

The organic synthetic dyes employed in industries are carcinogenic and harmful. Dyes must be removed from wastewater to limit or eliminate their presence before dumping into the natural environment. The current study aims to investigate the use of MgO nanoparticles to eliminate basic fuchsine (BF), as a model cationic dye pollutant, from wastewater. The MgO nanorods were synthesized through a coprecipitation method. The obtained nanocomposite was characterized using various techniques such as X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), Brunauer-Emmett-Teller (BET), and FTIR spectroscopy. It was found that the variation of dye concentration and pH influenced the removal of BF by MgO. The adsorption capacity of 493.90 mg/g is achieved under optimum operating conditions (pH = 11, contact time = 236 min, and initial BF concentration = 200 ppm). Pseudo-second-order adsorption kinetics and Freundlich isotherm models best fitted BF sorption onto MgO nanorods. The BF sorption mechanism is associated with the electrostatic attractions and hydrogen bond between the O-H group of MgO and the NH2 groups of BF, as indicated by the pH, isotherms, and FTIR studies. The reusability study indicates that MgO was effectively used to eliminate BF in at least four continuous cycles. The investigation of MgO with different dyes suggests the high adsorption selectivity of BF, crystal violet (CV), and malachite green (MG) dyes compared with methyl orange (MO) dye. Overall, MgO nanorods can act as a potential and promising adsorbent for the efficient and rapid removal of cationic dyes (CV, MG, and BF) from wastewater.

DFT-D4 Insight into the Inclusion of Amphetamine and Methamphetamine in Cucurbit[7]uril: Energetic, Structural and Biosensing Properties.

The host-guest interactions of cucurbit[7]uril (CB[7]) as host and amphetamine (AMP), methamphetamine (MET) and their enantiomeric forms (S-form and R-form) as guests were computationally investigated using density functional theory calculations with the recent D4 atomic-charge dependent dispersion corrections. The analysis of energetic, structural and electronic properties with the aid of frontier molecular orbital analysis, charge decomposition analysis (CDA), extended charge decomposition analysis (ECDA) and independent gradient model (IGM) approach allowed to characterize the host-guest interactions in the studied systems. Energetic results indicate the formation of stable non-covalent complexes where R-AMP@CB[7] and S-AMP@CB[7] are more stable thermodynamically than R-MET@CB[7] and S-MET@CB[7] in gas phase while the reverse is true in water solvent. Based on structural analysis, a recognition mechanism is proposed, which suggests that the synergistic effect of van der Waals forces, ion-dipole interactions, intermolecular charge transfer interactions and intermolecular hydrogen bonding is responsible for the stabilization of the complexes. The geometries of the complexes obtained theoretically are in good agreement with the X-ray experimental structures and indicate that the phenyl ring of amphetamine and methamphetamine is deeply buried into the cavity of CB[7] through hydrophobic interactions while the ammonium group remains outside the cavity to establish hydrogen bonds with the portal oxygen atoms of CB[7].

A Dispersion Corrected DFT Investigation of the Inclusion Complexation of Dexamethasone with ß-Cyclodextrin and Molecular Docking Study of Its Potential Activity against COVID-19.

The encapsulation mode of dexamethasone (Dex) into the cavity of ß-cyclodextrin (ß-CD), as well as its potential as an inhibitor of the COVID-19 main protease, were investigated using density functional theory with the recent dispersion corrections D4 and molecular docking calculations. Independent gradient model and natural bond orbital approaches allowed for the characterization of the host-guest interactions in the studied systems. Structural and energetic computation results revealed that hydrogen bonds and van der Waals interactions played significant roles in the stabilization of the formed Dex@ß-CD complex. The complexation energy significantly decreased from -179.50 kJ/mol in the gas phase to -74.14 kJ/mol in the aqueous phase. A molecular docking study was performed to investigate the inhibitory activity of dexamethasone against the COVID-19 target protein (PDB ID: 6LU7). The dexamethasone showed potential therapeutic activity as a SARS CoV-2 main protease inhibitor due to its strong binding to the active sites of the protein target, with predicted free energy of binding values of -29.97 and -32.19 kJ/mol as calculated from AutoDock4 and AutoDock Vina, respectively. This study was intended to explore the potential use of the Dex@ß-CD complex in drug delivery to enhance dexamethasone dissolution, thus improving its bioavailability and reducing its side effects.

Evaluation of a new series of pyrazole derivatives as a potent epidermal growth factor receptor inhibitory activity: QSAR modeling using quantum-chemical descriptors.

Pyrazole derivatives correspond to a family of heterocycle molecules with important pharmacological and physiological applications. At present, we perform a density functional theory (DFT) calculations and a quantitative structure-activity relationship (QSAR) evaluation on a series of 1-(4,5-dihydro-1H-pyrazol-1-yl) ethan-1-one and 4,5-dihydro-1H-pyrazole-1-carbothioamide derivatives as an epidermal growth factor receptor (EGFR) inhibitory activity. We thus propose a virtual screening protocol based on a machine-learning study. This theoretical model relates the studied compounds' biological activity to their calculated physicochemical descriptors. Moreover, the linear regression function is used to validate the model via the evaluation of Q2ext and Q2cv parameters for external and internal validations, respectively. Our QSAR model shows a good correlation between observed activities IC50 and predicted ones. Our model allows us to mitigate time-consuming problems and waste chemical and biological products in the preclinical phases.

An expanded halogen bonding scale using astatine.

As a non-covalent interaction, halogen bonding is now acknowledged to be useful in all fields where the control of intermolecular recognition plays a pivotal role. Halogen-bond basicity scales allow quantification of the halogen bonding of referential donors with organic functional groups from a thermodynamic point of view. Herein we present the pK BAtI basicity scale to provide the community an overview of halogen-bond acceptor strength towards astatine, the most potent halogen-bond donor element. This experimental scale is erected on the basis of complexation constants measured between astatine monoiodide (AtI) and sixteen selected Lewis bases. It spans over 6 log units and culminates with a value of 5.69 ± 0.32 for N,N,N',N'-tetramethylthiourea. On this scale, the carbon π-bases are the weakest acceptors, the oxygen derivatives cover almost two-thirds of the scale, and sulphur bases exhibit the highest AtI basicity. Regarding the applications of 211At in targeted radionuclide therapy, stronger labelling of carrier agents could be envisaged on the basis of the pK BAtI scale.

Adsorption Behavior of Congo Red onto Barium-Doped ZnO Nanoparticles: Correlation between Experimental Results and DFT Calculations.

Ba-loaded ZnO nanoparticles (Ba/ZnO) were obtained by the co-precipitation process and employed as a sorbent for Congo Red (C32H22N6Na2O6S2) dye (CR). Physicochemical parameters such as particle size, pH, and contact time were checked to characterize the adsorption process. The maximum adsorption capacity of Ba/ZnO NPs for CR (1614.26 mg/g) proves its potential utility in the elimination of CR dye from wastewater. The adsorption mechanism was studied via infrared spectroscopy and density functional theory calculations. The geometrical parameters and electronic properties of the CR-Ba/ZnO complex, particularly the interaction energy, the density of states, and the charge transfer, highlighted the Ba-ion mediation in the chemical bond formation between CR and the surface. The interaction between CR and Ba-doped ZnO has found to show strong chemisorption with charge transfer between the SO3- group and adsorbed Ba2+ ion on the surface.

p-Trifluoromethyl- and p-pentafluorothio-substituted curcuminoids of the 2,6-di[(E)-benzylidene)]cycloalkanone type: Syntheses and activities against Leishmania major and Toxoplasma gondii parasites.

A series of the title curcuminoids with structural variance in the heteroatom of the cycloalkanone and the p-substituents of the phenyl rings were tested for their activities against Leishmania major and Toxoplasma gondii parasites. The majority of them showed high activities against both parasite forms with EC50 values in the sub-micromolar concentration range. Bis(p-pentafluorothio)-substituted 3,5-di[(E)-benzylidene]piperidin-4-one 1b was not just noticeable antiparasitic, but also exhibited a considerable selectivity for L. major promastigotes over normal Vero cells. While derivatives differing only in the p-phenyl substituents being CF3 or SF5 showed similar antiparasitic activities, the cyclic ketone hub was more decisive both for the anti-parasitic activities and the selectivities for the parasites vs. normal cells. QSAR calculations confirmed the observed structure-activity relations and suggested structural variations for a further improvement of the antiparasitic activity. Docking studies based on DFT calculations revealed L. major pteridine reductase 1 as a likely molecular target protein of the title compounds.

Delocalized relativistic effects, from the viewpoint of halogen bonding.

The ability of organic and inorganic compounds bearing both iodine and astatine atoms to form halogen-bond interactions is theoretically investigated. Upon inclusion of the relativistic spin-orbit interaction, the I-mediated halogen bonds are more affected than the At-mediated ones in many cases. This unusual outcome is disconnected from the behavior of iodine's electrons. The significant decrease of astatine electronegativity with the spin-orbit coupling triggers a redistribution of the electron density, which propagates relativistic effects toward the distant iodine atom. This mechanism can be controlled by introducing suitable substituents and, in particular, strengthened by taking advantage of electron-withdrawing inductive and mesomeric effects. Noticeable relativistic effects can actually be transferred to light atoms properties, e.g., the halogen-bond basicity of bridgehead carbon atoms doubled in propellane derivatives.

Structural, electronic, and energetic investigations of acrolein adsorption on B36 borophene nanosheet: a dispersion-corrected DFT insight.

The adsorption of acrolein (AC) onto the surface of B36 borophene nanosheet was studied using dispersion-corrected density functional theory (DFT). The structural and electronic properties were scrutinized by several quantum chemical parameters such as HOMO-LUMO gap, condensed Fukui function, molecular electrostatic potential (ESP), and the density of states (DOS). The non-covalent interactions (NCI) were explored by combined reduced density gradient (RDG-NCI) and energy decomposition analysis (EDA) techniques. It was found that the adsorption of acrolein on both convex and concave surfaces of borophene is mainly governed by van der Waals interactions. Our calculations showed that the adsorption energy is strengthened and favored when multiple acrolein molecules adsorb on the edge sides of borophene through their terminal carbonyl oxygen atom. Furthermore, the calculated HOMO-LUMO energy gaps were significantly reduced upon adsorption affecting, therefore, the electrical conductance of borophene. These results should be useful in designing acrolein sensors.

Structural and energetic investigation on the host/guest inclusion process of benzyl isothiocyanate into ß-cyclodextrin using dispersion-corrected DFT calculations.

The formation of host-guest complex between benzyl isothiocyanate (BITC) and ß-cyclodextrin (ß-CD) was studied using dispersion-corrected density functional theory calculations. The complexation process was monitored using molecular docking simulations, natural bond orbital (NBO) technique, nuclear magnetic resonance (1H NMR) chemical shift calculations and non-covalent interactions (NCI) analysis. All these approaches are consistent with experimental findings. The calculated complexation energy was negative indicating the formation of inclusion complex. The most stable complexation of BITC involves the inclusion of its aromatic moiety in ß-CD cavity (model A) in accord with experimental NMR chemical shift data. The non-covalent interactions (NCI) based on the reduced density gradient (RDG) analysis reveal that mainly weak Van der Waals intermolecular interactions between BITC and ß-CD provide and ensure stability for the complexation process.

Spin-orbit coupling as a probe to decipher halogen bonding.

The nature of halogen-bond interactions is scrutinized from the perspective of astatine, the heaviest halogen element. Potentially the strongest halogen-bond donor, its ability is shown to be deeply affected by relativistic effects and especially by the spin-orbit coupling. Complexes between a series of XY dihalogens (X, Y = At, I, Br, Cl and F) and ammonia are studied with two-component relativistic quantum calculations, revealing that the spin-orbit interaction leads to a weaker halogen-bond donating ability of the diastatine species with respect to diiodine. In addition, the donating ability of the lighter halogen elements, iodine and bromine, in the AtI and AtBr species is more decreased by the spin-orbit coupling than that of astatine. This can only be rationalized from the evolution of a charge-transfer descriptor, the local electrophilicity ω+S,max, determined for the pre-reactive XY species. Finally, the investigation of the spin-orbit coupling effects by means of quantum chemical topology methods allows us to unveil the connection between the astatine propensity to form charge-shift bonds and the astatine ability to engage in halogen bonds.

Highly Selective Polypyrrole MIP-Based Gravimetric and Electrochemical Sensors for Picomolar Detection of Glyphosate.

There is a global debate and concern about the use of glyphosate (Gly) as an herbicide. New toxicological studies will determine its use in the future under new strict conditions or its replacement by alternative synthetic or natural herbicides. In this context, we designed biomimetic polymer sensing layers for the selective molecular recognition of Gly. Towards this end, complementary surface acoustic wave (SAW) and electrochemical sensors were functionalized with polypyrrole (PPy)-imprinted polymer for the selective detection of Gly. Their corresponding limits of detection were on the order of 1 pM, which are among the lowest values ever reported in literature. The relevant dissociation constants between PPy and Gly were estimated at [Kd1 = (0.7 ± 0.3) pM and Kd2 = (1.6 ± 1.4) µM] and [Kd1 = (2.4 ± 0.9) pM and Kd2 = (0.3 ± 0.1) µM] for electrochemical and gravimetric measurements, respectively. Quantum chemical calculations permitted to estimate the interaction energy between Gly and PPy film: ΔE = -145 kJ/mol. Selectivity and competitivity tests were investigated with the most common pesticides. This work conclusively shows that gravimetric and electrochemical results indicate that both MIP-based sensors are perfectly able to detect and distinguish glyphosate without any ambiguity.