From Conventional Prodrugs to Prodrugs Designed by Molecular Orbital Methods
Pp. 187-249 (63)
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.
Ab initio calculations, DFT calculations, enzyme models, molecular
mechanics calculations, prodrugs, prodrugs design.
Department of Bioorganic & Pharmaceutical Chemistry, College of Pharmacy, Al-Quds University, P. O. Box 20002, Jerusalem, Palestine.