Jump to main content
Jump to site search

Issue 10, 2015
Previous Article Next Article

Insights into the impact of N- and O-methylation on aqueous solubility and lipophilicity using matched molecular pair analysis

Author affiliations

Abstract

The impact of N- and O-methylation on chromatographically measured lipophilicity and high throughput chemiluminescent nitrogen detection (CLND) aqueous solubility was studied using matched molecular pairs for data sets of amides, sulfonamides, ureas, carbamates, amines, carboxylic acids, alcohols and phenols. The extent to which solubility and lipophilicity are affected by N- or O-methylation is dependent on the nature of atoms and substituents around the nitrogen or oxygen atom. In some classes of amides, N-methylation unexpectedly increases solubility and lowers log D7.4 considerably: this behaviour can be rationalised by conformational changes accompanying N-methylation that increase polar surface area, or by the disruption of one or more intramolecular hydrogen bonding motifs. Unlike amides, sulfonamide N-methylation always reduces solubility and increases lipophilicity, which again can be understood in terms of conformational effects. As expected, methylation of carboxylic acids lowers solubility and increases lipophilicity due to masking of the ionisable acidic group; however the magnitude of the reduction in solubility depends to some extent on the lipophilicity and molecular weight of the compound pairs under investigation.

Graphical abstract: Insights into the impact of N- and O-methylation on aqueous solubility and lipophilicity using matched molecular pair analysis

Back to tab navigation

Supplementary files

Publication details

The article was received on 23 Jul 2015, accepted on 19 Aug 2015 and first published on 21 Aug 2015


Article type: Concise Article
DOI: 10.1039/C5MD00309A
Author version
available:
Download author version (PDF)
Citation: Med. Chem. Commun., 2015,6, 1787-1797

  •   Request permissions

    Insights into the impact of N- and O-methylation on aqueous solubility and lipophilicity using matched molecular pair analysis

    T. J. Ritchie, S. J. F. Macdonald and S. D. Pickett, Med. Chem. Commun., 2015, 6, 1787
    DOI: 10.1039/C5MD00309A

Search articles by author

Spotlight

Advertisements