Prodrugs Design Based on Inter‐ and Intramolecular Chemical Processes

Abstract

This review provides the reader a concise overview of the majority of prodrug approaches with the emphasis on the modern approaches to prodrug design. The chemical approach catalyzed by metabolic enzymes which is considered as widely used among all other approaches to minimize the undesirable drug physicochemical properties is discussed. Part of this review will shed light on the use of molecular orbital methods such as DFT, semiempirical and ab initio for the design of novel prodrugs. This novel prodrug approach implies prodrug design based on enzyme models that were utilized for mimicking enzyme catalysis. The computational approach exploited for the prodrug design involves molecular orbital and molecular mechanics (DFT, ab initio, and MM2) calculations and correlations between experimental and calculated values of intramolecular processes that were experimentally studied to assign the factors determining the reaction rates in certain processes for better understanding on how enzymes might exert their extraordinary catalysis.

Antibacterial Prodrugs to Overcome Bacterial Resistance

“…The prodrug approach is now very popular, and it is not just used to alter the physicochemical parameters but is also used to alter many molecular and cellular factors such as influx/efflux membrane transporters and the expression/distribution of cellular proteins, in addition to drug targeting and delivery to enhance treatment and therapeutic efficacy [4][5][6][7][8][9]. Most of the β-lactam antibiotics are poorly absorbed, and the prodrug approach was used to improve their oral bioavailability.Pivampicillin (1) ( Figure 2) is an ampicillin derivative that is considered one of the first prodrugs to be developed, which is enzymatically hydrolyzed by esterases to give the active drug ampicillin, with inactive pivalic acid.…”

The prodrug approach in the era of drug design

“…For example, DFT and MM methods we have researched the mechanisms for the intramolecular proton transfer in Kirby's acetals and Bruice's cyclization of dicarboxylic semiesters which led to the design and synthesis of the following novel prodrugs: azanucleosides prodrugs for the treatment for myelodysplastic syndromes, tranexamic acid prodrugs for the treatment of hemorrhage conditions, dopamine prodrugs for Parrkinson's disease, atovaquone prodrugs as antimalarial agents, bitterless paracetamol prodrugs as antipyretic and pain killer for pediatrics and geriatrics, and prodrugs of the decongestant phenylephrine. In the above-mentioned examples, the prodrug linker was bound to the amine or hydroxyl group in the parent drug in such a way that the drug-linker entity (prodrug) intraconverts upon an exposure to the physiological environment such as stomach, intestine, and/or blood circulation, with intramolecular reaction rates that are only determined on the chemical structural features of the pharmacologically inactive promoiety (linker) [18].…”

Biomedical Applications of Aromatic Azo Compounds

“…The active drug and the nontoxic promoiety are released by internal or external stimuli in a targeted site within the body. A series of publication about prodrug concept is already presented by Karaman's group [15][16][17][18]. The cleavable character of azo bonds and their applications is recently reviewed by Mulu et al [19].…”