Succinylated isoniazid potential prodrug: Design of Experiments (DoE) for synthesis optimization and computational study of the reaction mechanism by DFT calculations

Abstract

Tuberculosis represents a worldwide public health concern, showing high rates of incidence and mortality annually. There is a recommended therapeutic regimen, in which isoniazid is indicated. This drug has a recognized action on Mycobacterium tuberculosis and presents pharmacokinetic problems, which can be improved using prodrug design. Considering that, this paper aimed to apply Design of Experiments (DoE) methods to optimize the synthetic procedure of succinylated isoniazid, a kind of isoniazid prodrug. For this reason, a factorial study 33, varying (1) reaction time (X1) at 6, 12 and 18 h; (2) proportion of excess succinic anhydride (X2) at 1.2, 1.4 and 1.6 equivalents and (3) the different catalysts (X3), pyridine, triethylamine and DMAP were carried out in 19 different experiments (performed in triplicate). It was observed that the condition containing DMAP, 18 h of reaction, presented the best result (85% yield). Additionally, DFT calculations were extremely important for understanding two competitive reaction mechanisms: via a basic DMAP catalysis (Pathway 1) and via self-catalyzed by the succinylated isoniazid (Pathway 2). The presence of a base was fundamental to generate a catalytic amount of product in order to start the Pathway 2. As the reaction goes on and the self-catalyst concentration increases, the Pathway 2 becomes the favorable mechanism, explaining the low influence of the base in the factorial test.