Benzylamines: synthesis and evaluation of antimycobacterial properties

Meindl, Wolfgang; Angerer, E. von; Schönenberger, Helmut; Ruckdeschel, G.

doi:10.1021/jm00375a005

Cited by 56 publications

(21 citation statements)

References 1 publication

(1 reference statement)

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“…The (4-methylbenzyl)alkylamines (6-12 in Table 1) were synthesized according to the literature. 30) All other compounds were obtained from Sigma-Aldrich, Steinheim, Germany; Carl Roth, Karlsruhe, Germany; and VWR, Leuven, Belgium in the highest available purity. Distilled water, HPLC grade methanol (Alfa Aesar, Karlsruhe, Germany) and 1-octanol (Sigma-Aldrich) were used throughout.…”

Section: Methodsmentioning

confidence: 99%

Lipophilicity Measurement of Drugs by Reversed Phase HPLC over Wide pH Range Using an Alkaline-Resistant Silica-Based Stationary Phase, XBridgeTM Shield RP18

et al. 2008

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The lipophilicity of solutes, conventionally expressed by their partition coefficient in the 1-octanol/water system (log P oct ), is of high significance from both physicochemical and pharmacological viewpoints.1,2) A number of intermolecular forces between a solute and its environment (i.e., solvents) determine the partitioning process and its equilibration. In pharmacology, the forces are particularly important because they control the migration of solutes (drugs) to biomembranes. Not a few studies have been reported on the relationship between log P oct and adsorption/permeation of drugs in cell cultures and/or tissue preparations. 3-7)The reference procedure to measure log P oct is shake-flask method. The method is, however, time-consuming and narrow in applicable range (ca. Ϫ3Ͻlog PϽ4). The reversedphase HPLC (RP-HPLC) came to be a promising alternative to the shake-flask method, because it has advantages such as high throughput rate (which is of key importance to pharmaceutical industry with a vast number of potential drug candidates), insensitivity to impurities and/or degradation products, broad applicable range, low sample consumption, good accuracy and automation possibilities. In RP-HPLC, lipophilicity indices are derived from the capacity factor log k, which is calculated from Eq. 1,where t r and t 0 are the retention times of the solute and of an unretained compound, respectively. Some workers have used isocratic log k values, measured in an appropriate mobile phase, as a lipophilicity parameter. 8-10) However, the majority of investigators use the capacity factors extrapolated to the 100% water (log k w ) condition in order to eliminate the effects of organic solvent.11-15) Indeed, the log k W has been proved to be useful for the investigation of a series of solutes covering broad lipophilicity range. Generally, the extrapolation is based on a quadratic relationship between the isocratic capacity factor log k and the volume fraction of organic solvent in the mobile phase, j.16) When methanol is used as an organic modifier, a linear relationship (Eq. 2) is often obtained for neutral solutes, 17,18) log kϭϪSjϩlog k wwhere S and log k w are the slope and the intercept of the regression curve, respectively. Until recently, most lipophilicity studies based on RP-HPLC had employed octadecyl silica (ODS) stationary phases 19,20) and silanol deactivated stationary phases. 15,21,22) As for ODS stationary phases, the correlations between log P oct and log k w (or log k) are generally good for structurally related solutes. 19,20) The decrease in correlation between them with increasing structural diversity of solutes is attributed to the specific interactions between the compounds and the residual silanol groups in such stationary phases. 23)Some studies have been done on silanol deactivated stationary phases, Supelcosil LC-ABZ and Discovery RP Amide C18, where their alkyl chains contain amide groups that electrostatically shield silanols from highly polar analytes. High correlations were found between log P ...

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Section: Methodsmentioning

confidence: 99%

Lipophilicity Measurement of Drugs by Reversed Phase HPLC over Wide pH Range Using an Alkaline-Resistant Silica-Based Stationary Phase, XBridgeTM Shield RP18

et al. 2008

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“…The alkyl(4-methylbenzyl)amines (1 -7 in the Table) were synthesized according to known procedures [27]. All other test compounds were obtained from commercial sources (Sigma-Aldrich, DSteinheim; Carl Roth, D-Karlsruhe; VWR, B-Leuven) in the highest available purity.…”

Section: Experimental Partmentioning

confidence: 99%

Drug–Membrane Interaction on Immobilized Liposome Chromatography Compared to Immobilized Artificial Membrane (IAM), Liposome/Water, and Octan‐1‐ol/Water Systems

Liu

Fan

Chen

et al. 2010

Helvetica Chimica Acta

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The objective of this study was to investigate drug -membrane interaction by immobilized liposome chromatography (ILC; expressed as lipophilicity index log K s ) and the comparison with lipophilicity indices obtained by liposome/H 2 O, octan-1-ol/H 2 O, and immobilized artificial membrane (IAM) systems. A set of structurally diverse monofunctional compounds and drugs (nonsteroidal antiinflammatory drugs and b-blockers) were selected in this study. This set of solutes consists of basic or acidic functionalities which are positively or negatively charged at physiological pH 7.4. No correlation was found between log K s from ILC and lipophilicity indices from any of the other membrane model systems for the whole set of compounds. For structurally related compounds, significant correlations could be established between log K s from ILC and lipophilicity indices from IAM chromatography and octan-1-ol/H 2 O. However, ILC and liposome/H 2 O systems only yield parallel partitioning information for structurally related large molecules. For hydrophilic compounds, the balance between electrostatic and hydrophobic interactions dominating drug partitioning is different in these two systems.

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“…The (4-methylbenzyl)alkylamines 37 -43 (Table) were synthesized by known procedures [29]. All other compounds were obtained from commercial sources (Sigma -Aldrich, Steinheim, Germany; Carl Roth, Karlsruhe, Germany; VWR, Leuven, Belgium) in the highest available purity.…”

Section: Experimental Partmentioning

confidence: 99%

Retention Behavior of Neutral and Positively and Negatively Charged Solutes on an Immobilized‐Artificial‐Membrane (IAM) Stationary Phase

Liu

Hefesha

Scriba

et al. 2008

Helvetica Chimica Acta

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The retention behavior of neutral, positively charged, and negatively charged solutes on the IAM.PC.DD2 stationary phase was investigated and compared. A set of monofunctional compounds and complex drugs (steroids, nonsteroidal anti-inflammatory drugs, and b-blockers) were selected for this study, i.e., neutral solutes and solutes with acidic or basic functionalities which are positively charged or negatively charged at pH 7.0. The correlation between the retention factor log k w at pH 7.0 on the IAM.PC.DD2 stationary phase and the partition coefficient log P oct or the distribution coefficient log D 7.0 showed that the retention mechanism depends on the charge state and structural characteristics of the compounds. The neutrals were least retained on the IAM.PC.DD2 stationary phase, and positively charged solutes were more retained than negatively charged ones. This implies that the retention of the charged solutes is controlled not only by lipophilicity but also by the electrostatic interaction with the phospholipid, with which positively charged solutes interact more strongly than negatively charged ones.Introduction. -Successful drug development requires not only optimization of specific and potent pharmacological activity at the target site, but also efficient delivery to that site. Drug design and discovery must take pharmacokinetic behavior into account, in particular absorption and distribution. Numerous quantitative structurepermeability-relationship (QSPR) studies have clearly demonstrated that lipophilicity, as related to membrane partitioning and hence passive transcellular diffusion, is a key parameter in predicting and interpreting permeability [1] [2]. Lipophilicity is generally expressed by the octan-1-ol/H 2 O partition coefficient (log P oct , for a single chemical species) or distribution coefficient (log D oct , for a pH-dependent mixture of ionizable compounds). In some studies, a relationship has been established between log P oct (or log D oct ) and the absorption or permeability in intestinal models [3] [4], blood-brainbarrier models [5], and cell-culture models [6 -9], to name a few. However, in many other situations, log P oct (or log D oct ) cannot give a good estimate of a drugs absorption or permeation [10 -14]. The lipophilicity parameters log P oct or log D oct fail to encode some important recognition forces, most notably ionic bonds, which are of particular importance when modeling the interaction of ionized compounds with biomembranes [15]. Because the majority of the drugs are ionizable [16], any prediction of their pharmacodynamic and pharmacokinetic properties should take their ionization into account.

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Benzylamines: synthesis and evaluation of antimycobacterial properties

Cited by 56 publications

References 1 publication

Lipophilicity Measurement of Drugs by Reversed Phase HPLC over Wide pH Range Using an Alkaline-Resistant Silica-Based Stationary Phase, XBridgeTM Shield RP18

Lipophilicity Measurement of Drugs by Reversed Phase HPLC over Wide pH Range Using an Alkaline-Resistant Silica-Based Stationary Phase, XBridgeTM Shield RP18

Drug–Membrane Interaction on Immobilized Liposome Chromatography Compared to Immobilized Artificial Membrane (IAM), Liposome/Water, and Octan‐1‐ol/Water Systems

Retention Behavior of Neutral and Positively and Negatively Charged Solutes on an Immobilized‐Artificial‐Membrane (IAM) Stationary Phase

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