Oleg A. Raevsky

Quantitative estimation of hydrogen bond contribution to permeability and absorption processes of some chemicals and drugs

Abstract The H-bond donor and acceptor descriptors Σ C d and Σ C a , which are estimated directly from thermodynamic data ofhydrogen bonding, were successfully used for the correlation with permeability and absorption data for some chemicals and drugs. The evaluation of different types of permeability test systems and of different classes of compounds showed that in addition to steric bulk effects both the H-bond donor and acceptor strength play an important role in explaining differences in permeability and absorption of neutral chemical compounds and drugs. However, because of the frequently observed intercorrelation between Σ C d and Σ C a , often only the more significant of them leads to a significant regression coefficient in multiple linear regression equations. In comparison with Σ C d and/or Σ C a less significant correlations are obtained with the experimental parameter Δlog P (the difference between the octanol/water partition coefficient log P Oct and log P for the system alkane or cyclohexane/water) which has to be considered as a composed descriptor containing H-bond donor as well as H-bond acceptor effects.

Estimating the water solubilities of crystalline compounds from their chemical structures alone.

Partial atomic charges are significant descriptors in predicting the water solubilities of crystalline organic compounds from their chemical structures. Lipophilicity remains the predominant factor. It was also found that quantitative estimates of hydrogen bond strengths (hydrogen bond factors) play important roles. These descriptors can be easily interpreted to guide chemists to the synthesis of compounds with increased or decreased water solubility. This work is based on a set of 22 compounds the aqueous solubilities of which were determined by a new potentiometric method, pSOL, and were confirmed, in part, by the traditional shake-flask method. A new software package, HYBOTPLUS, furnished the partial atomic charges and hydrogen bond factors.

Crown Ether–Ammonium Complexes: Binding Mechanisms and Solvent Effects

Thermodynamics of 18-crown-6 complexes with ammonium cations (NH4, MeNH3, Me2NH2, Me3NH, Me4N, Et4N, PhNH3, and PhCH2NH3 ) in methanol were determined by titration calorimetry. The results show strong contributions from entropy terms counteracting the enthalpy of complexation, and a linear decrease of the complexation free energy ΔG with the number of available N–H hydrogen bonds. In several cases formation of relatively strong complexes containing two ammonium ions per crown unit was observed. Tetramethylammonium ions show no detectable association with the crown ether, demonstrating the absence of significant Coulomb-type interaction between the partial charges at the crown ether oxygen and the N+–C–H atoms. Ammonium ions bind to aza crown ethers with almost equal affinity as to the all-oxygen anologs only, if methyl groups at the nitrogen atoms force the lone pairs into equatorial position. Molecular mechanics calculations (CHARMm) of corresponding gas-phase complexes yield geometries and energies in agreement with this, with energetically equally good conformations of an essentially undistorted D3d crown accepting either 3 linear hydrogen bonds, or 6 bifurcated bonds from the primary ammonium cations. Complexation equilibria were measured with PhNH3, and PhCH2NH3 in water, 2-propanol, tert-butyl alcohol, n-octanol, DMF, DMSO, pyridine, HMPT and acetone mostly by calorimetry, in some cases by potentiometry. The observed association constants varied by factors of up to 1000; the solvent effects can be described generally as a linear function of the hydrogen bond accepting power of the solvent molecules, in line with the mechanisms derived above. The lgK and ΔH values of the complexation of the PhNH3 or PHCH2NH3 cation with 18-crown-6 ligand are compared with a large range of available solvent properties. The best correlations (R ≈ 0.9) for lgK (or ΔG) are obtained with values characterizing the electron donor capacity of the solvent (Ca, β*, DN) for lgK, as found earlier for complexes between K+ and 18C6.

QSAR Studies of Compounds Acting by Polar and Non‐polar Narcosis: an Examination of the Role of Polarisability and Hydrogen Bonding

The toxicities of 33 non-polar narcotics and 15 polar narcotics have been correlated with the logarithm of the octanol-water partition coefficient (log P). Correlations have also been obtained of toxicities with polarisabilities (α) and free energy hydrogen bond acceptor factors (Ca) calculated using HYBOT-PLUS. There are clear differences in the way non-polar and polar narcotics correlate with log P and with α and Ca, indicating that the two classes of compound exert their toxicity by somewhat different mechanisms.

N-(4-Chloro­phen­yl)benzene­sulfonamide

The crystal structure of the title compound, C12H10ClNO2S, has been determined. The molecules of the substance form chains with adjacent molecules by means of hydrogen bonds, which create infinite helicoids along the b axis. The hydrogen-bond network can be described by the graph-set as C(4) (infinite chain with four atoms in the repeat pattern).

A Novel Approach for Prediction of Intestinal Absorption of Drugs in Humans based on Hydrogen Bond Descriptors and Structural Similarity

A new approach to predict the intestinal absorption of drugs in humans is presented. It is based on structural similarity and hydrogen bonding properties (ΣC values) of drug-like compounds. The relationship between gastrointestinal absorption in humans and hydrogen bond descriptors for 100 structurally diverse drugs was studied. From the sigmoid relationship for passively transported drugs it could be concluded that those with ΣC values less than 14 were completely absorbed, whereas those with ΣC values higher than 18 were poorly absorbed. In cases where other transport mechanisms prevail due to special structural features, an absorption threshold can be significantly different. So, instead of including the whole set of compounds in the QSAR analyses, small subsets of 1 to 5 structurally related drugs (nearest neighbors of a drug of interest) estimated by means of similarity calculations were considered. The contribution of the passive transport component and the corresponding influence of hydrogen bond factors on absorption was assumed to be similar within the postulated subsets.

3D hydrogen bond thermodynamics (HYBOT) potentials in molecular modelling

A new approach is proposed to more accurately estimate the energies of H-bond interactions in three-dimensional (3D) molecular modelling. The approach is based on the use of H-bond acceptor and donor enthalpy factor values calculated by means of program HYBOT, the use of a sigmoid relationship to determine the optimum H-bond distances and established force-field methods to determine distance and angle dependencies. The base-pair interactions in a short A-form RNA double-helix are presented as an example of enthalpy calculations of hydrogen bonding for a model system.

pH‐Dependent Partitioning of Acidic and Basic Drugs into Liposomes—A Quantitative Structure‐Activity Relationship Analysis

The partitioning of drugs in the phospholipid liposome/water system has often been used as a model for the investigation of drug/cell membrane interactions. Generally distribution/pH profiles for acidic and basic compounds observed in the phospholipid/water system cannot be predicted by profiles obtained in the octanol/water system. This is true especially for pH regions where acids and bases are ionized. Based on the well-known pH-partition theory our nonlinear regression analysis of published pH-dependent liposome-water distribution coefficients of 18 basic and acidic drugs resulted in equations with satisfactory predictive power. Surprisingly the separate equations describing the partitioning of neutral, anionic or cationic drugs into phosphatidylcholine liposomes are rather similar with respect to significant physicochemical properties and their regression coefficients. Despite being differently charged the distribution of all three species into the phospholipid bilayer increases with size/bulk (polarizability α) and decreases with polarity characterized by the sum of substructural partial charges. Furthermore, for the neutral compounds and their cations an unfavorable effect of H-bond acceptor strength on distribution is found. Unexpectedly the H-bond donor effect of neutral or ionized species does not seem to influence their liposome partitioning behavior (as observed within each group of neutral, cationic or anionic drugs). Generally the distribution of ionizable molecules into phospholipid bilayers decreases with increasing degree of ionization. In this data set it was found for the first time that specific N-H-acidic drugs may show the opposite behavior. Obviously anions with a delocalized negative charge like anions of tautomeric pyrimidinones/pyrimidinols have the possibility to enter into some strong special interaction with phospholipid molecules.

Steric and Stereoelectronic Effects in Aza Crown Ether Complexes[1]

Stability constants and enthalpy changes determined by calorimetric titrations and supported by selected NMR titrations are reported for the complexation of sodium and potassium cations with 18 different crown ethers containing nitrogen atoms with different number, location and substitution pattern. The data, measured in methanol mostly with potassium salts, are compared to literature data; they show striking differences between all-oxygen analogs and the macrocycles with NH groups. In contrast, affinities with aza crown ethers bearing alkyl groups at the nitrogen as well as with the cryptand [2.2.2] come closer to the complexation free energies predicted from the number and electron donating capacity of the ligand heteroatoms. This is rationalised on the basis of molecular mechanics calculations, showing that a NH-containing crown predominates in conformations with axial N lone pairs, due to their repulsive electrostatic interactions with the ring oxygen atoms. Replacement of the hydrogen by alkyl groups forces the lone pairs to an equatorial position, thus enabling better complex formation, as borne out by experiment. In line with these arguments the lgK differences are with some exceptions more due to ΔH than to TΔS differences. The calorimetric data show linear isoequilibrium correlations between TΔS and ΔH, with slopes between those observed with other crown ether and cryptand complexes. Preliminary investigations of some synthetic macrocyclic amide precursors yield appreciable complexation only, if the two carbonyl oxygens can come in close contact with the guest cation. Computer aided molecular modelling shows that this is possible in a small 15C5-derivative, in which the polyethylenglycol cycle only serves as ring template without binding contributions from the ether oxygen atoms.

Thermodynamic and structural aspects of sulfonamide crystals and solutions

The crystal structures of three sulfonamides with the general structure 4-NH(2)-C(6)H(4)-SO(2)NH-C(6)H(4/3)-R (R = 4-Et; 4-OMe; 5-Cl-2-Me) have been determined by X-ray diffraction. On the basis of our previous data and the results obtained a comparative analysis of crystal properties was performed: molecular conformational states, packing architecture, and hydrogen bond networks using graph set notations. The thermodynamic aspects of the sulfonamide sublimation process have been studied by investigating the temperature dependence of vapor pressure using the transpiration method. A regression equation was derived describing the correlation between sublimation entropy terms and crystal density data calculated from X-ray diffraction results. Also correlations between sublimation Gibbs energies and melting points, on the one hand, and between sublimation enthalpies and fusion enthalpies at 298 K, on the other hand, were found. These dependencies give the opportunity to predict sublimation thermodynamic parameters by simple thermo-physical experiments (fusion characteristics). Solubility processes of the compounds in water, n-hexane, and n-octanol (as phases modeling various drug delivery pathways and different types of membranes) were investigated and corresponding thermodynamic functions were calculated as well. Thermodynamic characteristics of sulfonamide solvation were evaluated. For compounds with similar structures processes of transfer from one solvent to another one were studied by a diagram method combined with analysis of enthalpic and entropic terms. Distinguishing between enthalpy and entropy, as is possible through the present approach, leads to the insight that the contribution of these terms is different for different molecules (entropy- or enthalpy-determined). Thus, in contrast to interpretation of only the Gibbs energy of transfer, being extensively used for pharmaceuticals in the form of the partition coefficient (log P), the analysis of thermodynamic functions of the transfer process provides additional mechanistic information. This may be important for further evaluation of the physiological distribution of drug molecules and may provide a better understanding of biopharmaceutical properties of drugs.