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Falasteen Salameh, Donia Karaman, Gennaro Mecca, Laura Scrano, Sabino A. Bufo and Rafik Karaman*


The classical approach for delivery of drugs into the central nervous system (CNS) is associated with adverse effects and it has many limitations. Therefore, extensive efforts have been done in searching and developing novel methods for achieving such delivery. This mini-review discusses the design and synthesis of selected targeting prodrugs for the treatment of conditions related to impairment in the CNS such as Parkinson‘s and Alzheimer‘s diseases. Such approaches include targeting prodrugs which are designed to interact with unique cellular conditions at the target site, especially the availability of certain enzymes and transporters at these sites. In addition, part of this mini-review is devoted to prodrugs design based on enzyme models that have been invoked to understand how enzymes catalyzebiotransformation. In this approach, the prodrugs design isdone using quantum molecular orbital and molecular mechanics methods. The equations obtained from correlations of experimental and calculated rate values for some intramolecular processes are used to predict parameters for other intramolecular processes that can be utilized as prodrugs linkers. In this approach, there is no need for enzymes to catalyze the conversion of the prodrug to its active parent drug and the conversion rate of the prodrug is dependent only on those factors playing dominant role in the rate-limiting step of the process.

Keywords: Prodrugs, Targeted prodrugs, CNS, Parkinson‘s disease, Dopamine, Alzheimer‘s disease, Intramolecularity, Enzyme models.

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