Hydrogen Bond Donor Properties Research Articles

Tautomers of 2,4-dihydro-3H-1,2,4-triazol-3-one and their Composites with NTO - A DFT Treatment

In the present density functional study, some tautomers of 2,4-dihydro-3H-1,2,4-triazol-3-one (1,2-dihydro-1,2,4-triazol-3-one) and their composites formed with NTO have been considered within the constraints of the density functional theory and the basis set employed (B3LYP/6-311++G(d,p)). The triazolone considered is the precursor of NTO in various methods. It may exhibit 1,3-proton tautomerism. Various energies, QASR, quantum chemical and spectral properties have been harvested and discussed. All the considered species have exothermic heat of formation and favorable Gibbs free energy of formation values at the standard states and they are stable electronically. Although most of the composites considered exhibit a directed interaction between their partners, one of them possesses perpendicular (T-type) orientation. Certain hydrogen bondings between the tautomers and NTO occur at different extents, depending on the particular tautomer involved in the composite. Both of the components have hydrogen bond donor and acceptor properties except composite NTO+T2, in which the tautomer is the hydrogen bond donor and NTO is the acceptor. The tautomers absorb in the UV region of the spectrum like NTO, whereas in all the composites appreciable changes in the appearance of the spectra happen and certain degree of bathochromic effect occurs as compared to the respective spectra of the partners.

Empirical Hydrogen Bonding Donor (HBD) Parameters of Organic Solvents Using Solvatochromic Probes - A Critical Evaluation.

The solvatochromicity of established solvatochromic UV/Vis probes, which appear to be sensitive to the so-called hydrogen bond donor (HBD) property of the solvent, is analysed using the hydroxyl group density of alcoholic solvents DHBD as a physical parameter in comparison to the pKa, the chemical benchmark for acidity. Reichardt's dye B30, Kosowers Z-indicator 1-ethyl-4-(methoxycarbonyl) pyridinium iodide (K), Kamlet-Tafts α, Dragos S parameter, Catalans SA scale, the cis-dicyano-bis (1,10-phenanthroline) iron II complex (Schilt's Ferrocyphen dye, Fe) and Gutmann's acceptor number (AN) have been investigated. The observed dependencies of the empirical polarity parameters as a function of DHBD for several alcoholic solvent families requires a ompletely new physicochemical understanding of these established HBD parameters. Only the AN scale (or Fe) is able to bridge the gap between global polarity and acidity, provided the values are interpreted correctly and applied accordingly.

Phenolic compounds as α-glucosidase inhibitors: a docking and molecular dynamics simulation study

Phenolic compounds possess significant biological activity. Several pieces of research emphasize the medicinal importance of phenolic compounds, including diabetes. The present study investigated the α-glucosidase inhibitory activity of phenolic compounds reported from several plants. The phenolic compounds reported in different literature were collected. Molecular docking was carried out using AutoDock Vina. Various physicochemical properties such as size, LogP, molecular complexity, hydrogen bonding properties of phenolic compounds were correlated with the binding affinities. Furthermore, MD simulation was carried out to study the structural stability of the docking complexes. A total of 155 phenolic compounds were reported from different plants. Amentoflavone showed the strongest binding affinity with α-glucosidase, much more potent than reference acarbose. The binding energy showed a good correlation with the molecular complexity, hydrogen bond donor and acceptor property and heavy atom counts of the compounds. The polarity of the surface area also showed a positive correlation with the binding affinity of the compounds. The best docking phenolic compound, amentoflavone, showed stable binding affinity and conformation during the simulation period compared to apoprotein and acarbose-docking complex. The top ten phenolic compounds, including amentoflavone, showed considerable drug-likeness properties with fewer toxicity effects. The study suggests that the amentoflavone could be a potential therapeutic drug as an α-glucosidase inhibitor and help control postprandial hyperglycemia. Communicated by Ramaswamy H. Sarma

Docking-Based 3D-QSAR Studies for 1,3,4-oxadiazol-2-one Derivatives as FAAH Inhibitors

This work aimed to construct 3D-QSAR CoMFA and CoMSIA models for a series of 31 FAAH inhibitors, containing the 1,3,4-oxadiazol-2-one moiety. The obtained models were characterized by good statistical parameters: CoMFA Q2 = 0.61, R2 = 0.98; CoMSIA Q2 = 0.64, R2 = 0.93. The CoMFA model field contributions were 54.1% and 45.9% for steric and electrostatic fields, respectively. In the CoMSIA model, electrostatic, steric, hydrogen bond donor, and hydrogen acceptor properties were equal to 34.6%, 23.9%, 23.4%, and 18.0%, respectively. These models were validated by applying the leave-one-out technique, the seven-element test set (CoMFA r2test-set = 0.91; CoMSIA r2test-set = 0.91), a progressive scrambling test, and external validation criteria developed by Golbraikh and Tropsha (CoMFA r20 = 0.98, k = 0.95; CoMSIA r20 = 0.98, k = 0.89). As the statistical significance of the obtained model was confirmed, the results of the CoMFA and CoMSIA field calculation were mapped onto the enzyme binding site. It gave us the opportunity to discuss the structure–activity relationship based on the ligand–enzyme interactions. In particular, examination of the electrostatic properties of the established CoMFA model revealed fields that correspond to the regions where electropositive substituents are not desired, e.g., in the neighborhood of the 1,3,4-oxadiazol-2-one moiety. This highlights the importance of heterocycle, a highly electronegative moiety in this area of each ligand. Examination of hydrogen bond donor and acceptor properties contour maps revealed several spots where the implementation of another hydrogen-bond-donating moiety will positively impact molecules’ binding affinity, e.g., in the neighborhood of the 1,3,4-oxadiazol-2-one ring. On the other hand, there is a large isopleth that refers to the favorable H-bond properties close to the terminal phenoxy group of a ligand, which means that, generally speaking, H-bond acceptors are desired in this area.

Characterization of the new CelerisTM Arginine column: Retentive behaviour through a combination of chemometric tools and potential in drug analysis

CelerisTM Arginine (ARG) is a mixed-mode stationary phase recently released on the market. To characterize its analytical behavior, the retention factors of a pool (n=100, of which 36 neutrals, 26 acids and 38 bases) of pharmaceutically relevant compounds have been measured on this phase over eight percentages (from 10 to 90% v/v) of acetonitrile (MeCN) as organic modifier. The ARG phase exhibited enhanced affinity for the molecules that are in their anionic form at the experimental pH, whilst basic compounds, albeit over a wide range of lipophilicity and pKa values, were on average poorly retained. To dissect the separation mechanism of the ARG phase, the overall analytical retention has been deconvoluted into the individual contributions of intermolecular forces by a QSPR/ Partial Least Square (PLS)/Block Relevance (BR) analysis tool recently developed by us.For the neutrals, the most relevant blocks were found to be Size, describing the interaction due to the dimension of the molecule, and O, representing the solute's hydrogen bond donor properties. The change in sign from positive to negative of the Size block, which occurs between 10% and 20% MeCN, allowed to visually appreciate the switch in the separation mode from reversed phase to normal phase. Some good statistic models for rationalizing the analytical behaviour of neutrals were developed from VS+ descriptors. However, their performance in modelling the analytical retention of acids was substandard, probably due to the intrinsic inefficacy of VS+ descriptors in handling electric charges. This instance was addressed by a complimentary MLR strategy, which led to successfully model the retention of acids on the ARG column and to shed light into their retention mechanism, which seemed to be substantially driven by electrostatics.

Thermodynamic evidence for nano-heterogeneity in solutions of the macrocycle C-butylresorcin[4]arene in non-aqueous solvents

Partial molar volumes and isentropic compressibilities of the macrocyclic calixarene C-butylresorcin[4]arene have been determined as functions of solute concentration and temperature in five non-aqueous solvents of widely differing character: ethanol, 1-propanol, acetonitrile, N,N-dimethylformamide and dimethylsulfoxide. Both thermodynamic parameters indicated the presence of solute aggregation in all of the studied solvents. Detailed analysis of the data implied that the aggregates formed contained significant amounts of solvent, suggesting that the solutions were nano-heterogeneous rather than conventional micellar. Differences among the solvents were consistent with their hydrogen-bond donor and acceptor properties.

Exploiting the Strong Hydrogen Bond Donor Properties of a Borinic Acid Functionality for Fluoride Anion Recognition

AbstractBorinic acids have typically not been considered as hydrogen bond donor groups in molecular recognition. Described herein is a bifunctional borane/borinic acid derivative (2) in which the two functionalities are connected by a 1,8‐biphenylenediyl backbone. Anion binding studies reveal that 2 readily binds a fluoride anion by formation of a unique B−F⋅⋅⋅H−O−B hydrogen bond. This hydrogen bond is characterized by a short H‐F distance of 1.79(3) Å and a large coupling constant (1JHF) of 57.2 Hz. The magnitude of this interaction, which has also been investigated computationally, augments the fluoride anion binding properties of 2, thus making it compatible with aqueous environments.

Exploiting the Strong Hydrogen Bond Donor Properties of a Borinic Acid Functionality for Fluoride Anion Recognition.

Borinic acids have typically not been considered as hydrogen bond donor groups in molecular recognition. Described herein is a bifunctional borane/borinic acid derivative (2) in which the two functionalities are connected by a 1,8-biphenylenediyl backbone. Anion binding studies reveal that 2 readily binds a fluoride anion by formation of a unique B-F⋅⋅⋅H-O-B hydrogen bond. This hydrogen bond is characterized by a short H-F distance of 1.79(3) Å and a large coupling constant (1 JHF ) of 57.2 Hz. The magnitude of this interaction, which has also been investigated computationally, augments the fluoride anion binding properties of 2, thus making it compatible with aqueous environments.

An Effective Gluten Extraction Method Exploiting Pure Choline Chloride-Based Deep Eutectic Solvents (ChCl-DESs)

Gluten analysis is still affected by the lack of an efficient and universal extraction solvent for gliadin, i.e., the prolamine fraction of gluten which is the analytical target used to quantify gluten in food. In this investigation, the possibility of adopting pure choline chloride deep eutectic solvents (ChCl-DESs) as gliadin extraction media was tested. As prototypes of ChCl-DESs, ethaline and reline were chosen in view of their good dipolar and hydrogen bond donor (HBD) properties, as well as of their moderate enough viscosity. Their ability to act as effective solvents for gliadin and their inability to affect the subsequent gliadin detection by a frequently adopted and commercially available ELISA kit were first assessed. Ethaline and reline extraction performance was then tested by evaluating gliadin recoveries achieved on gluten-free food real samples before and after their spiking with controlled gliadin amounts. Higher recoveries were found by using these DESs in comparison with those gained by the usually adopted 60% (v/v) ethanol-water solvent. In fact, gluten recoveries ranging from 78 to 113%, with a RSD better than 13%, were achieved by using ethaline. Less good recoveries (from 67 to 132% with a RSD of 20%) were achieved with reline, even though they were however better than those found with 60% v/v ethanol-water solvent. These results make the proposed media profitable solvents for gliadin extraction and its subsequent detection by a commonly used immunoassay kit, without any change of the usual detection procedure.

Intramolecular Hydrogen Bond Reverting the Solvent Effect on Phosphorus Hyperfine Coupling Constants of β-Phosphorylated Nitroxides.

Recently, we reported a dramatic solvent effect on the phosphorus hyperfine coupling constant aP of β-phosphorylated six-membered ring nitroxides, that is, approximately 25 G of difference in aP from n-hexane to water (Org. Biomol. Chem. 2016, 14, -1228-1292). In this article, we report on the effect of intramolecular hydrogen bonding (IHB) in three nitroxides exhibiting IHB between the hydroxyl and diethylphosphoryl groups and one exhibiting IHB between the hydroxyl group and the nitroxyl moiety. It is observed that for the first three nitroxides, aP increases with increasing polarity/polarizability and hydrogen bond donor (HBD) properties of the solvent (π* and α, respectively)-in sharp contrast to the data reported in the literature-and for the last nitroxide, aP decreases with π* and α. In fact, the occurrence of IHB induces a large strain, its suppression by hydrogen bond acceptor (HBA) solvents affords an increase in aP .

Antioxidant properties in a non-polar environment of difluoromethyl bioisosteres of methyl hydroxycinnamates.

Many natural antioxidants have poor pharmacokinetic properties that impair their therapeutic use. For hydroxycinnamic acids (HCAs) and other phenolic antioxidants, their major drawback is their low lipophilicity and a rapid metabolism. The difluoromethyl group may be considered as a 'lipophilic hydroxyl' due to its hydrogen bond donor and acceptor properties; this prompted us to assess it as a bioisosteric replacement of a phenolic hydroxyl for increasing the lipophilicity of HCAs. Six difluoromethyl-substituted methyl cinnamates (4a-c, 5a-c) related to caffeic acid were synthesized and their antioxidant activity evaluated by chemical (FRAP, DPPH scavenging, inhibition of β-carotene bleaching, at 1-200μm), electrochemical (differential pulse voltammetry, cyclic voltammetry) and cell-based (inhibition of lipid peroxidation in erythrocytes, at 1 and 50μm) assays. Analogues 4a-c and 5a-c were inactive in FRAP and DPPH assays and only those containing a free phenolic hydroxyl (4a and 5a) exhibited electrochemical activity although with high redox potentials. Compounds 4a,b and 5a,b were active in the inhibition of β-carotene bleaching assay and all analogues inhibited lipid peroxidation in the human erythrocytes assay. Lipophilic difluoromethyl-substituted cinnamic esters retain radical scavenging capabilities that prove useful to confer antioxidant properties in a non-polar environment.

Quantitative structure–permeability relationships at various pH values for acidic and basic drugs and drug-like compounds

Absorption in gastrointestinal tract compartments varies and is largely influenced by pH. Therefore, considering pH in studies and analyses of membrane permeability provides an opportunity to gain a better understanding of the behaviour of compounds and to obtain good permeability estimates for prediction purposes. This study concentrates on relationships between the chemical structure and membrane permeability of acidic and basic drugs and drug-like compounds. The membrane permeability of 36 acidic and 61 basic compounds was measured using the parallel artificial membrane permeability assay (PAMPA) at pH 3, 5, 7.4 and 9. Descriptive and/or predictive single-parameter quantitative structure-permeability relationships were derived for all pH values. For acidic compounds, membrane permeability is mainly influenced by hydrogen bond donor properties, as revealed by models with r2 > 0.8 for pH 3 and pH 5. For basic compounds, the best (r2 > 0.7) structure–permeability relationships are obtained with the octanol–water distribution coefficient for pH 7.4 and pH 9, indicating the importance of partition properties. In addition to the validation set, the prediction quality of the developed models was tested with folic acid and astemizole, showing good matches between experimental and calculated membrane permeabilities at key pHs. Selected QSAR models are available at the QsarDB repository (http://dx.doi.org/10.15152/QDB.166).

A Complementary Study of Mechanisms and Behaviors in Chromatography via Modeling.

Evolution in preparation of chromatographic columns has created the need for studying and evaluating them with the use of smart software. This research is an attempt to compare the retention mechanism between two stationary phases (butyl and phenyl) with the use of multivariate analysis for a large number of probes. Partial least squares has the ability to spot either major or minor differences in the chromatographic behavior of probes, with regard to changes in the stationary or mobile phases. The models developed refer to a total of 108 miscellaneous chemical compounds, described by 63 X variables (physicochemical properties and structural features) and one Y variable (retention time). The results showed that in both columns and mobile phases (40% methanol or 40% acetonitrile) the retention of an analyte is mainly affected by its lipophilicity, molar volume, and refractivity, which tend to cause delayed elution. On the contrary, solubility in water, polar surface area, and hydrogen bond donor or acceptor properties promote faster elution. The most important difference proved to be the effect of the presence of the carboxylic group and the solubility that affected the retention in a similar way in both columns but not with both mobile phases.

Chemometric design to explore pharmacophore features of BACE inhibitors for controlling Alzheimer's disease.

The β-amyloid precursor protein cleavage enzyme (BACE) has been conceived to be an attractive therapeutic target to control Alzheimer's disease (AD). Validated ligand-based pharmacophore mapping was combined with 3D QSAR modeling approaches that include CoMFA, CoMSIA and HQSAR techniques to identify structural and physico-chemical requirements for a potential BACE inhibitor using a database containing 980 structurally diverse compounds, assembled from different reports. A structure-based docking technique was also used to validate the features obtained from the ligand-based models, which were further used to screen the database of compounds designed by a de novo approach. Contour maps of 3D QSAR models, CoMFA (R(2) = 0.880, se = 0.402, Q(2) = 0.596, Rpred(2) = 0.713,) and CoMSIA (R(2) = 0.903, se = 0.362, Q(2) = 0.578, Rpred(2) = 0.715), and a pharmacophore space model (R(2) = 0.833, rmsd = 1.578, Q(2) = 0.845, Rpred(2) = 0. 764) depict that the models are robust and provide an explanation of the important features such as steric, electrostatic, hydrophobic, positive ionization, hydrogen bond acceptor and donor properties, which play important roles for interaction with the receptor site cavity. The HQSAR study (R(2) = 0.823, se = 0.488, Q(2) = 0.823, Rpred(2) = 0.768) and de novo design, which generate new fragments, illustrated the important molecular fingerprints for inhibition. The docking study elucidated the important interactions between the amino acid residues (Gly11, Thr72, Asp228, Gly230, Thr231, Arg235) at the catalytic site of the receptor and the ligand, indicating the structural requirements of the inhibitors. The de novo designed molecules were further screened for ADMET properties, and ligand-receptor interactions of the top hits were analysed by molecular docking to explore pharmacophore features of BACE inhibitors.

The Block Relevance (BR) analysis supports the dominating effect of solutes hydrogen bond acidity on Δlog Poct–tol

The role of hydrogen bond acidity, i.e., the ability of chemicals to act as hydrogen bond donors (HBD), is a crucial element in pharmaceutical sciences and medicinal chemistry. It has been shown that the difference between logP values (ΔlogP) obtained in two different biphasic systems is informative of the solutes HBD properties and thus useful in the prediction of drugs human fate.In this study, we collected from literature more than 200 experimental logPtol (the logarithm of the partition coefficient P in the toluene/water system) values along with their corresponding logPoct (the logarithm of the partition coefficient P in the octanol/water system) values. The dataset was processed using a purposely-built in-house software to remove molecules that are potentially able to form IMHBs. On the remaining structures the ΔlogPoct–tol (=logPoct – logPtol) have been calculated and correlated with 82 VolSurf+descriptors through a PLS model. Finally the Block Relevance (BR) analysis has been used to group the descriptors in six easy-to-interpret blocks and to show graphically the relevance of a certain block in the PLS model.BR analysis showed that the hydrogen bond donor (HBD) properties of the solutes mainly govern ΔlogPoct–tol. This supports the use of ΔlogPoct–tol to estimate HBD properties of solutes and its role in the intramolecular hydrogen bonding (IMHB) interpretation scheme recently reported in the literature.

Chemically Triggered C–ON Bond Homolysis in Alkoxyamines. 6. Effect of the Counteranion

We showed (J. Org. Chem. 2012, 77, 9634) that the activation by methylation of pyridyl-based alkoxyamine 1 increased with the hydrogen bond donor properties of solvents. In this paper, activation of 1 by protonation with acids, CF3COOH and CSA, in tert-butylbenzene (t-BuPh) and in H2O/MeOH afforded, with CF3COOH, k(d) 28-fold larger in H2O/MeOH than in t-BuPh, whereas it was only 4-fold larger when CSA was used. This puzzling observation was ascribed to the dissociation of the intimate ion pair.

Preparation and evaluation at the delta opioid receptor of a series of linear leu-enkephalin analogues obtained by systematic replacement of the amides.

Leu-enkephalin analogues, in which the amide bonds were sequentially and systematically replaced either by ester or N-methyl amide bonds, were prepared using classical organic chemistry as well as solid phase peptide synthesis (SPPS). The peptidomimetics were characterized using competition binding, ERK1/2 phosphorylation, receptor internalization, and contractility assays to evaluate their pharmacological profile over the delta opioid receptor (DOPr). The lipophilicity (LogD7.4) and plasma stability of the active analogues were also measured. Our results revealed that the last amide bond can be successfully replaced by either an ester or an N-methyl amide bond without significantly decreasing the biological activity of the corresponding analogues when compared to Leu-enkephalin. The peptidomimetics with an N-methyl amide function between residues Phe and Leu were found to be more lipophilic and more stable than Leu-enkephalin. Findings from the present study further revealed that the hydrogen-bond donor properties of the fourth amide of Leu-enkephalin are not important for its biological activity on DOPr. Our results show that the systematic replacement of amide bonds by isosteric functions represents an efficient way to design and synthesize novel peptide analogues with enhanced stability. Our findings further suggest that such a strategy can also be useful to study the biological roles of amide bonds.

Pharmacophore modeling and 3D-QSAR (CoMSIA) studies for structural requirements of some triazine derivatives as G-quadruplex binders for telomerase inhibition

Human telomeres are repetitive guanine rich sequences found at the ends of chromosomes that form special secondary structures known as G-quadruplexes. In majority of cancer cells, the telomerase enzyme has been found to maintain the length of telomeres, conferring cell immortality and prevention of cell senescence. Small molecules that bind and stabilize the G-quadruplex have proved to be potential telomerase inhibitors. The quantitative structure–activity relationships of triazine derivatives as G-quadruplex mediating telomerase inhibitors remain unclear. The objective of the study is to uncover structural requirements for triazine derivatives as G-quadruplex binders, which would eventually assist and complement the rational drug-design attempts for successful development of telomerase inhibitors as anticancer drugs. The model has been established by using a training set of compounds with cross-validated q2 0.593, non-cross-validated r2 0.976, standard error of estimate 0.167, and F test 115.130 for the best CoMSIA model. The predictive ability of the models was validated with the correlation coefficient rpred2 0.738 for the best CoMSIA model. The highly predictive 3D-model resulting from this study discovers the roles played by molecular features, mainly steric, hydrogen bond donor and hydrophobic properties.

Smoothed Gaussian molecular fields: an evaluation of molecular alignment problems

Several smoothed Gaussian-based descriptors used in a molecular superposition algorithm are presented. One descriptor, as detailed in a previous work (Leherte in J Comput Chem 27:1800–1816, 2006), is the full electron density approximated through the promolecular atomic shell approximation (PASA) (Amat and Carbo-Dorca in J Chem Inf Comput Sci 40:1188–1198, 2000). Herein, we additionally present a new descriptor, that is, the charge density of a molecule calculated via the Poisson equation. The Coulomb potential as approximated by Good et al. (J Chem Inf Comput Sci 32:188–191, 1992) and atom-based functions such as hydrogen bond donor or acceptor properties, lipophilicity as detailed in the work of Totrov (Chem Biol Drug Des 71:15–27, 2008) were also considered. A Monte Carlo/Simulated Annealing superposition method is applied to a set of six families of drug molecules, that is, elastase inhibitors, ligands of endothiapepsins, trypsins, thermolysins, p38 MAP kinases, and rhinovirus, all of them already reported in the literature, for discussing superposition problems. The results show that the descriptor selection can be guided by the nature of the interactions expected to occur between the drug molecules and their receptor. They also emphasize the particular efficiency of the PASA descriptor for molecules characterized by significant shape properties.

Crystallographic Signatures of N6-Methoxyadenine Imino Tautomer–Silver Complexes

Detailed crystallographic analysis of four silver complexes of N9-benzyl-N6-methoxyadenine, 1, on the basis of three different counteranions and silver ion stoichiometry, is discussed in this article. 1 is a rare tautomer of adenine, which exhibits promutagenic behavior as it partly mimics hydrogen bond donor and acceptor properties of guanine and mispairs with cytosine. Complexes 2 and 4 exhibit discrete Ag2L2 dimer, while complex 3 shows two AgL2 units in addition to a Ag2L2 dimer, all in a head-to tail fashion. Complex 5, on the other hand, shows four AgL2 units coordinated in a head-to-head fashion affording a three-dimensional lattice stabilized by CH···F interactions. Various noncovalent interactions such as hydrogen bonding, CH-π interactions, argentophilic interactions, and Ag-π interactions stabilize these complexes.