Population, Acid−Base, and Redox Properties ofN-Acetylcysteine Conformers

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Abstract
Rotamers of N-acetyl-l-cysteine (NAC, the most popular mucolytic drug) are characterized in terms of populations, site- and conformer-specific acid−base properties, reducing strength, and molecular pharmacology. A new, general relationship between the bulk- and rotamer-specific basicities is introduced. NAC at high pH predominantly exists in a trans thiolate−carboxylate rotameric form, whereas protonation promotes the occurrence of intramolecular hydrogen bond-forming isomers. Distribution curves of the rotamers are depicted as a function of pH. Rotamer-dependent thiolate basicities differ by up to 0.5 log k units. Carboxylate basicities show slight conformation-dependence only. The membrane-penetrating capabilities from various compartments of the body are assessed on the basis of the pH-dependent charge of the molecule. The thiol−disulfide half-cell potential is calculated, using the correlation between the thiolate basicity and oxidizability. The oxidation−reduction properties of NAC are compared to those of other biological thiols in their definite microscopic forms. The pharmacokinetic behavior is interpreted in terms of the physicochemical parameters, providing molecular/submolecular explanation for several therapeutic properties of NAC.