Linear Free Energy Relationship (LFER) Analysis of Dissociation Constants of 8-Hydroxyquinoline and Its Derivatives in Aqueous and Dioxane–Water Solutions

Robak, Waldemar; Apostoluk, Wiesław; Maciejewski, Paweł; Pielka, Julia Agnieszka; Kwiotek, Joanna Natalia

doi:10.1021/je3009045

Cited by 1 publication

(2 citation statements)

References 85 publications

(124 reference statements)

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“…Further support for this conclusion comes from the calculated lowest-energy cluster geometries; many of the 7-substituted 2-methylquinolin-8-ol derivatives exhibit structures that suggest the possibility of intramolecular hydrogen bonding (see Supporting Information ). 9 Moreover, our findings here are supported by past studies where the effects of electron-donating and electron-withdrawing substituents (and their respective σ or σ + constants) on p K a 23 , 24 , 26 , 29 and solubility 30 , 32 have been examined for quinoline-8-ol derivatives. Ultimately, this apparent influence of electronic effects on DMS separation suggests a connection to linear free energy relationship and possibly to quantitative structure–activity relationships (QSAR).…”

Section: Results and Discussionsupporting

confidence: 89%

“…In this study, we employed DMS–MS to examine drug molecules that shared a common core: 2-methylquinolin-8-ol (Scheme ). This drug and its analogues have been employed for years in a variety of pharmaceutical applications and physicochemical studies. − In total, we examined 22 drug molecules: 7 triplets of isomers (each bearing one of 7 functional groups in either the 5-, 6-, or 7-position of the quinoline ring) as well as 2-methylquinolin-8-ol itself. One of the reasons for choosing this model drug chemistry was that several types of structural motifs are present that could impact the microsolvation, as well as the bulk physicochemical properties of these molecules; the different functional groups provide opportunities for varied steric and electronic effects to be present, as well as the presence of intramolecular hydrogen bonds (IMHBs), that could also impact the behavior of these molecules.…”

Section: Results and Discussionmentioning

confidence: 99%

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Assessing Physicochemical Properties of Drug Molecules via Microsolvation Measurements with Differential Mobility Spectrometry

Liu¹,

Blanc²,

Schneider³

et al. 2017

ACS Cent. Sci.

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The microsolvated state of a molecule, represented by its interactions with only a small number of solvent molecules, can play a key role in determining the observable bulk properties of the molecule. This is especially true in cases where strong local hydrogen bonding exists between the molecule and the solvent. One method that can probe the microsolvated states of charged molecules is differential mobility spectrometry (DMS), which rapidly interrogates an ion’s transitions between a solvated and desolvated state in the gas phase (i.e., few solvent molecules present). However, can the results of DMS analyses of a class of molecules reveal information about the bulk physicochemical properties of those species? Our findings presented here show that DMS behaviors correlate strongly with the measured solution phase pKa and pKb values, and cell permeabilities of a set of structurally related drug molecules, even yielding high-resolution discrimination between isomeric forms of these drugs. This is due to DMS’s ability to separate species based upon only subtle (yet predictable) changes in structure: the same subtle changes that can influence isomers’ different bulk properties. Using 2-methylquinolin-8-ol as the core structure, we demonstrate how DMS shows promise for rapidly and sensitively probing the physicochemical properties of molecules, with particular attention paid to drug candidates at the early stage of drug development. This study serves as a foundation upon which future drug molecules of different structural classes could be examined.

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