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Although drugs currently used for the various types of diseases (e.g., antiparasitic, antiviral, antibacterial, etc.) are effective, they present several undesirable pharmacological and pharmaceutical properties. Most of the drugs have low bioavailability, lack of sensitivity, and do not target only the damaged cells, thus also affecting normal cells. Moreover, there is the risk of developing resistance against drugs upon chronic treatment. Consequently, their potential clinical applications might be limited and therefore, it is mandatory to find strategies that improve those properties of therapeutic agents. The development of prodrugs using amino acids as moieties has resulted in improvements in several properties, namely increased bioavailability, decreased toxicity of the parent drug, accurate delivery to target tissues or organs, and prevention of fast metabolism. Herein, we provide an overview of models currently in use of prodrug design with amino acids. Furthermore, we review the challenges related to the permeability of poorly absorbed drugs and transport and deliver on target organs.

The development of new drugs is a lengthy and complex process regarding its conception and ideation, passing through in silico studies, synthesis, in vivo studies, clinical trials, approval, and commercialization, with an exceptionally low success rate. The lack of efficacy, safety, and suboptimal pharmacokinetic parameters are commonly identified as significant challenges in the discovery of new drugs. To help address these challenges, various approaches have been explored in medicinal chemistry, including the use of prodrug strategies. As a well-established approach, prodrug design remains the best option for improving physicochemical properties, reducing toxicity, and increasing selectivity, all while minimizing costs and saving on biological studies. This review article aims to analyze the current advances using the prodrug approach that has allowed the advance of drug candidates to clinical trials in the last 10 years. The approaches presented here aim to inspire further molecular optimization processes and highlight the potential of this strategy to facilitate the advancement of new compounds to clinical study phases.

The discovery and development of new pharmaceutical drugs is a costly, time-consuming, and highly manual process, with significant challenges in ensuring drug bioavailability at target sites. Computational techniques are highly employed in drug design, particularly to predict the pharmacokinetic properties of molecules. One major kinetic challenge in central nervous system drug development is the permeation through the blood–brain barrier (BBB). Several different computational techniques are used to evaluate both BBB permeability and target delivery. Methods such as quantitative structure–activity relationships, machine learning models, molecular dynamics simulations, end-point free energy calculations, or transporter models have pros and cons for drug development, all contributing to a better understanding of a specific characteristic. Additionally, the design (assisted or not by computers) of prodrug and nanoparticle-based drug delivery systems can enhance BBB permeability by leveraging enzymatic activation and transporter-mediated uptake. Neuroactive peptide computational development is also a relevant field in drug design, since biopharmaceuticals are on the edge of drug discovery. By integrating these computational and formulation-based strategies, researchers can enhance the rational design of BBB-permeable drugs while minimizing off-target effects. This review is valuable for understanding BBB selectivity principles and the latest in silico and nanotechnological approaches for improving CNS drug delivery.

Using thyrotropin-releasing hormone (TRH) as a model, we explored whether synergistic combination of lipoamino acid(s) and a linker cleaved by prolyl oligopeptidase (POP) can be used as a promoiety for prodrug design for the preferential brain delivery of the peptide. A representative prodrug based on this design principle was synthesized, and its membrane affinity and in vitro metabolic stability, with or without the presence of a POP inhibitor, were studied. The in vivo formation of TRH from the prodrug construct was probed by utilizing the antidepressant effect of the peptide, as well as its ability to increase acetylcholine (ACh) synthesis and release. We found that the prototype prodrug showed excellent membrane affinity and greatly increased metabolic stability in mouse blood and brain homogenate compared to the parent peptide, yet a POP inhibitor completely prevented prodrug metabolism in brain homogenate. In vivo, administration of the prodrug triggered antidepressant-like effect, and microdialysis sampling showed greatly increased ACh release that was also antagonized upon a POP inhibitor treatment. Altogether, the obtained promising exploratory data warrant further investigations on the utility of the prodrug approach introduced here for brain-enhanced delivery of small peptides with neurotherapeutic potential.

This chapter focuses on the various prodrug approaches that have been used to overcome many of the pharmaceutical and pharmacokinetic barriers that hinder the optimal delivery of the active drug. The most important requirement in prodrug design is naturally the adequate reconversion of the prodrug to the active drug in vivo at the intended compartment. This prodrug‐drug conversion may take place before absorption, in the GI system, during absorption such as in the GI wall or skin, after absorption, or at the specific site of drug action. A number of enzymes can also be delivered to targeted tissues through antibodies or gene delivery approaches for the activation of subsequently administered prodrugs. Although they are of limited use in small‐molecule pro‐drugs, Schiff bases have been used to conjugate amine‐containing drugs to polymers with carbonyl groups as macromolecular prodrugs for slow release and targeting.

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.

Recently, World Health Organization (WHO) and Medicins San Frontieres (MSF) proposed a classification of diseases as global, neglected and extremely neglected. Global diseases, such as cancer, cardiovascular and mental (CNS) diseases represent the targets of the majority of the R&D efforts of pharmaceutical companies. Neglected diseases affect millions of people in the world yet existing drug therapy is limited and often inappropriate. Furthermore, extremely neglected diseases affect people living under miserable conditions who barely have access to the bare necessities for survival. Most of these diseases are excluded from the goals of the R&D programs in the pharmaceutical industry and therefore fall outside the pharmaceutical market. About 14 million people, mainly in developing countries, die each year from infectious diseases. From 1975 to 1999, 1393 new drugs were approved yet only 1% were for the treatment of neglected diseases [3]. These numbers have not changed until now, so in those countries there is an urgent need for the design and synthesis of new drugs and in this area the prodrug approach is a very interesting field. It provides, among other effects, activity improvements and toxicity decreases for current and new drugs, improving market availability. It is worth noting that it is essential in drug design to save time and money, and prodrug approaches can be considered of high interest in this respect. The present review covers 20 years of research on the design of prodrugs for the treatment of neglected and extremely neglected diseases such as Chagas’ disease (American trypanosomiasis), sleeping sickness (African trypanosomiasis), malaria, sickle cell disease, tuberculosis, leishmaniasis and schistosomiasis.

Bacterial resistance to present antibiotics is emerging at a high pace that makes the development of new treatments a must. At the same time, the development of novel antibiotics for resistant bacteria is a slow-paced process. Amid the massive need for new drug treatments to combat resistance, time and effort preserving approaches, like the prodrug approach, are most needed. Prodrugs are pharmacologically inactive entities of active drugs that undergo biotransformation before eliciting their pharmacological effects. A prodrug strategy can be used to revive drugs discarded due to a lack of appropriate pharmacokinetic and drug-like properties, or high host toxicity. A special advantage of the use of the prodrug approach in the era of bacterial resistance is targeting resistant bacteria by developing prodrugs that require bacterium-specific enzymes to release the active drug. In this article, we review the up-to-date implementation of prodrugs to develop medications that are active against drug-resistant bacteria.

Phosphonates, often used as isosteric replacements for phosphates, can provide important interactions with an enzyme. Due to their high charge at physiological pH, however, permeation into cells can be a challenge. Protecting phosphonates as prodrugs has shown promise in drug delivery. Thus, a variety of structures and cleavage/activation mechanisms exist, enabling release of the active compound. This review describes the structural diversity of these pro-moieties, relevant cleavage mechanisms and recent advances in the design of phosphonate prodrugs.