A computational study of pyrazinamide: tautomerism, acid–base properties, micro–solvation effects and acid hydrolysis mechanism

Abstract

Pyrazinamide (PZA) is a prodrug substance utilised in the treatment of tuberculosis related to mycobacterium strains. The activities of this compound are said to occur in acidic medium where it is converted to the active form of pyrazinoic acid. To better understand its molecular properties related to its ability to interact with other species in the body and to understand its reaction mechanism in acidic medium, the current study investigates conformational preferences, tautomerism, acid–base properties, interaction with explicit water solvent molecules as well as its hydrolysis in acidic medium. The study is performed utilising DFT/M06-2X, DFT/MPWB1K and the MP2 methods with several basis sets including 6-311+G(3df, 2p) and aug-cc-pVDZ. The results suggest that only the keto tautomeric form is stable and that its stability is strongly determined by the presence of intramolecular hydrogen bonds. The preferred site for protonation is the pyrazine nitrogen in meta position to the substituent group and the preferred site for deprotonation is the NH₂ group. The micro-solvated systems are stabilised by the interplay between intramolecular hydrogen bond and intermolecular hydrogen bonds. The acid hydrolysis mechanism is achieved through the protonation of the sp² O atom, the formation of the tetrahedral C atom, resulting in its pyramidalisation and eventual weakening of the Csingle bondN bond, protonation of the N atom in the NH₂ group, which is essential for the breaking of the Csingle bondN amide bond.