Determination of the permeability characteristics of two sulfenamide prodrugs of linezolid across Caco-2 cells.

The purpose of this work was to study the permeability of two relatively lipophilic sulfenamide prodrugs of linezolid (clogP 0.85), N-(phenylthio)linezolid (1, clogP 2.77) and N-[(2-ethoxycarbonyl)ethylthio]linezolid (2, clogP 1.

Reversion of sulfenamide prodrugs in the presence of free thiol-containing proteins.

The purpose of this work was to study the reaction kinetics between two model sulfenamide prodrugs of linezolid, N-(phenylthio)linezolid and N-[(2-ethoxycarbonyl)ethylthio]linezolid, with free thiol-containing proteins; commercial human serum albumin (HSA); a constitutively active mutant of the protein tyrosine phosphatase PRL-1 (PRL-1-C170S-C171S), a model protein; and diluted fresh human plasma. The reaction was followed by high-performance liquid chromatography, both for the loss of prodrug and appearance of linezolid, and at different pH values with molar excess of the proteins relative to the prodrugs. Pseudo first-order kinetics was observed.

In vitro conversion of model sulfenamide prodrugs in the presence of small molecule thiols.

Sulfenamide prodrugs of amide and urea functional group containing drugs have recently been proposed as a means of altering the physical and bioproperties of problematic drug molecules containing these two functionalities. Sulfenamides have been shown to revert to the parent drug via reaction with thiols. Explored here is the mechanism for this reaction.

Prodrug strategies to overcome poor water solubility.

Drug design in recent years has attempted to explore new chemical spaces resulting in more complex, larger molecular weight molecules, often with limited water solubility. To deliver molecules with these properties, pharmaceutical scientists have explored many different techniques. An older but time-tested strategy is the design of bioreversible, more water-soluble derivatives of the problematic molecule, or prodrugs.