From Conventional Prodrugs to Prodrugs Designed by Molecular Orbital Methods
- Pp. 187-249 (63)Rafik Karaman
In this chapter we attempt to present a novel prodrug approach which is based on enzyme models that have been advocated to understand the mechanism by which enzymes catalyze biochemical transformations. The tool exploited in the design of novel prodrugs is computational calculations using molecular orbital (MO) and molecular mechanics (MM) methods and correlations between experimental and calculated rate values for some intramolecular processes. In this approach, no enzyme is needed to catalyze the intraconversion of a prodrug to its active parent drug. The conversion rate is solely determined by the factors affecting the rate limiting step in the intramolecular (interconversion) process. Knowledge gained from unraveling the mechanisms of the studied enzyme models (cyclization of Bruice’s dicarboxylic semiesters and acid-catalyzed hydrolysis of Kirby’s N-alkylmaleamic acids) was exploited in the design. It is believed that the use of this approach might eliminate all disadvantages related to prodrug interconversion by the metabolic approach (enzyme catalyzed process). By utilizing this approach we have succeeded to design novel prodrugs for a number of commonly used drugs such as the anti-bleeding agent, tranexamic acid, the antihypertensive agent, atenolol, the pain killer agent, paracetamol, and the antibacterial agents, amoxicillin, cephalexin and cefuroxime. In vitro studies have shown that in contrast to the active drugs (atenolol, paracetamol, amoxicillin and cephalexin) which possess bitter sensation, the corresponding prodrugs were bitterless. Hence, it is expected that patient compliance especially in the pediatric and geriatric population will be significantly increased.