Population, acid-base, and redox properties of N-acetylcysteine conformers

Rotamers of N-acetyl-L-cysteine (NAC, the most popular mucolytic drug) are characterized in terms of populations, site- and conformer-specific acid-ba se properties, reducing strength, and molecular pharmacology. A new, genera l relationship between the bulk- and rotamer-specific basicities is introdu ced. NAC at high pH predominantly exists in a trans thiolate-carboxylate ro tameric form, whereas protonation promotes the occurrence of intramolecular hydrogen bond-forming isomers. Distribution curves of the rotamers are dep icted as a function of pH. Rotamer-dependent thiolate basicities differ by up to 0.5 log k units. Carboxylate basicities show slight conformation-depe ndence only. The membrane-penetrating capabilities from various compartment s of the body are assessed on the basis of the pH-dependent charge of the m olecule. The thiol-disulfide half-cell potential is calculated, using the c orrelation between the thiolate basicity and oxidizability. The oxidation-r eduction properties of NAC are compared to those of other biological thiols in their definite microscopic forms. The pharmacokinetic behavior is inter preted in terms of the physicochemical parameters, providing molecular/subm olecular explanation for several therapeutic properties of NAC.