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Pharmaceutics
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Prodrugs and Molecular Hybrids as Innovative Strategies in Medicinal Chemistry
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Prodrugs and Molecular Hybrids as Innovative Strategies in Medicinal Chemistry

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: 31 July 2025 | Viewed by 9097

Special Issue Editors

Prof. Dr. Loretta Lazzarato

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Guest Editor
Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
Interests: nitric oxide; NO-(photo)donors; molecular hybrid strategy; prodrug strategy; drug discovery; drug development
Special Issues, Collections and Topics in MDPI journals
Dr. Sodano Federica

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Guest Editor
1. Department of Pharmacy, University of Napoli Federico II, 80131 Napoli, Italy
2. Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
Interests: NO-(photo)donors; prodrug strategy; carbohydrate-based prodrugs; molecular hybrid design; drug design; drug delivery; drug targeting
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Maria Grazia Rimoli

E-Mail Website
Guest Editor
Department of Pharmacy, University of Napoli Federico II, 80131 Napoli, Italy
Interests: prodrug strategy; carbohydrate-based prodrugs; drug targeting; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Prodrug Design is a well-known strategy of chemically modifying the structure of a drug, which is called the "parent drug." This approach makes it possible to optimize the physiochemical and pharmacological properties of a parent drug, resulting in improvement of its pharmacokinetic characteristics and reduction of its toxicity.

Another innovative strategy used in medicinal chemistry is Molecular Hybridization. This is a new drug design and development concept based on combining pharmacophoric moieties of different bioactive substances to produce a new hybrid compound with improved affinity and efficacy compared with parent drugs. In addition, this approach can lead to compounds with a modified selectivity profile, different and/or dual modes of action, and reduced unwanted side effects.

In this Special Issue "Prodrugs and Molecular Hybrids as Innovative Strategies in Medicinal Chemistry", we aim to collect both original articles and up-to-date reviews that focus on the design, synthesis, physiochemical and biological characterization of novel prodrugs and/or molecular hybrids that have been shown to overcome many limitations related to the pharmaceutical, pharmacokinetics and/or pharmacodynamics phase of the parent drugs.

As Guest Editor, we encourage researchers working in this area to contribute their recent studies to this Special Issue of Pharmaceutics.

Prof. Dr. Loretta Lazzarato
Dr. Sodano Federica
Prof. Dr. Maria Grazia Rimoli
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • prodrugs
  • bioprecursors
  • carrier prodrugs
  • macromolecular prodrugs
  • mutual prodrugs
  • molecular hybrids
  • hybrid drugs
  • macromolecular hybrids
  • anti-inflammatory activity
  • antimicrobial activity
  • anticancer activity
  • biomedical applications
  • physicochemical characterization
  • pharmacokinetics profile
  • pharmacodynamics properties
  • drug targeting
  • drug delivery
  • drug discovery
  • drug development
  • toxicity

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Published Papers (6 papers)

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Research

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15 pages, 2799 KiB  
Article
PEGylation Effects on Amphiphilic Platinum(IV) Complexes: Influence on Uptake, Activation, and Cytotoxicity
by Arpit Sharma, Md Al Amin, Man B. Kshetri, Suha Alqarni, Wjdan Jogadi, Jordan Solmen, Zexin Lin, Shirin Akter and Yao-Rong Zheng
Pharmaceutics 2025, 17(4), 440; https://doi.org/10.3390/pharmaceutics17040440 - 29 Mar 2025
Viewed by 571
Abstract
Background/Objectives: The utilization of amphiphilic Pt(IV) complexes as prodrugs offers a promising strategy to revolutionize Pt-based cancer therapy by enhancing drug delivery and activation. While PEGylation is widely used to optimize drug properties, its impact on the biological behavior of amphiphilic Pt(IV) complexes [...] Read more.
Background/Objectives: The utilization of amphiphilic Pt(IV) complexes as prodrugs offers a promising strategy to revolutionize Pt-based cancer therapy by enhancing drug delivery and activation. While PEGylation is widely used to optimize drug properties, its impact on the biological behavior of amphiphilic Pt(IV) complexes remains unclear. This study systematically investigates how the PEGylation of varying molecular weights influences their cytotoxicity, cellular uptake, and activation. Methods: Pt(IV) complexes were synthesized with PEG chains of different molecular weights using HATU-catalyzed amide bond formation and copper-free click chemistry. Their biological properties were assessed through cell-based analyses, focusing on cytotoxicity, cellular uptake, and activation by biological reductants. Results: Small PEG modifications retained the potent cytotoxicity of amphiphilic Pt(IV) prodrugs, whereas large PEG chains significantly reduced efficacy. The decrease in potency was linked to impaired cellular uptake and mitochondrial accumulation. Additionally, large PEG modifications slowed the reduction and activation of Pt(IV) prodrugs by biological reductants, further limiting their anticancer activities. Conclusions: These findings underscore the critical role of PEGylation in metallodrug design and provide key insights into optimizing PEGylation strategies for enhancing platinum–based cancer therapies. Full article
(This article belongs to the Special Issue Prodrugs and Molecular Hybrids as Innovative Strategies in Medicinal Chemistry)
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15 pages, 2919 KiB  
Article
Toxicity, Half-Life and Antitumor Activity of Phenyl 4-(2-Oxo-3-alkylimidazolidin-1-yl)benzenesulfonates as Novel Antimitotic CYP1A1-Targeted Prodrugs in Female Mouse Models
by Atziri Corin Chavez Alvarez, Chahrazed Bouzriba, Vincent Ouellette, Mathieu Gagné-Boulet, Alexandre Patenaude, Sylvie Pilote, René C.-Gaudreault, Chantale Simard and Sébastien Fortin
Pharmaceutics 2025, 17(2), 233; https://doi.org/10.3390/pharmaceutics17020233 - 11 Feb 2025
Viewed by 731
Abstract
Background/Objectives: Chemoresistance of breast cancers (BCs) is a major impediment to current chemotherapeutics that urges the development of new drugs and new therapeutic approaches. To that end, phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) were recently prepared to fulfill some of the unmet needs with classic [...] Read more.
Background/Objectives: Chemoresistance of breast cancers (BCs) is a major impediment to current chemotherapeutics that urges the development of new drugs and new therapeutic approaches. To that end, phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) were recently prepared to fulfill some of the unmet needs with classic chemotherapeutics. PAIB-SOs are prodrugs bioactivated into potent antimitotics by the cytochrome P450 1A1 (CYP1A1), which is a frequent enzyme in resistant BC cells, but mostly missing in normal cells. Our screening program studies of PAIB-SO chemolibraries selected three prototypical PAIB-SOs as antimitotic prodrugs amenable for studies using BC animal models. Methods: Healthy female CD1® IGS mice were treated with three prototypical PAIB-SOs, namely CEU-835, -934, and -938, for the determination of their toxicity and half-lives. Moreover, MCF7 tumor-bearing CD1-Foxn1nu Nude female mice were treated with the three prototypical PAIB-SOs for the determination of their antitumor activity. Results: Herein, we show that multi-intravenous administrations of CEU-835, -934, and -938 at their maximal solubilities are well tolerated in healthy female CD1® IGS mice, as depicted by the evaluation of distress behaviors, organ necropsy, total blood cell count, and histology. Moreover, the half-life of CEU-835, -934, and -938 administered intravenously in healthy CD1® IGS female mice were 8.1, 23.2, and 21.5 h, respectively. Finally, their intravenous administrations of CEU-934 and -938 decreased MCF7 tumor growth as efficiently as paclitaxel in MCF7 tumor-bearing CD1-Foxn1nu Nude mouse model. Conclusions: overall, our study demonstrated for the first time that pentyl-bearing PAIB-SOs are new CYP1A1-dependent prodrugs efficiently decrease breast cancer tumor growth, and show no side effects at their pharmacological concentration in mouse models. Full article
(This article belongs to the Special Issue Prodrugs and Molecular Hybrids as Innovative Strategies in Medicinal Chemistry)
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15 pages, 2482 KiB  
Article
Pharmacokinetic Evaluation of Neutral Sphinghomyelinase2 (nSMase2) Inhibitor Prodrugs in Mice and Dogs
by Arina Ranjit, Chae Bin Lee, Lukáš Tenora, Vijaya Saradhi Mettu, Arindom Pal, Jesse Alt, Barbara S. Slusher and Rana Rais
Pharmaceutics 2025, 17(1), 20; https://doi.org/10.3390/pharmaceutics17010020 - 26 Dec 2024
Viewed by 960
Abstract
Background: Extracellular vesicles (EVs) can carry pathological cargo, contributing to disease progression. The enzyme neutral sphingomyelinase 2 (nSMase2) plays a critical role in EV biogenesis, making it a promising therapeutic target. Our lab previously identified a potent and selective inhibitor of nSMase2, [...] Read more.
Background: Extracellular vesicles (EVs) can carry pathological cargo, contributing to disease progression. The enzyme neutral sphingomyelinase 2 (nSMase2) plays a critical role in EV biogenesis, making it a promising therapeutic target. Our lab previously identified a potent and selective inhibitor of nSMase2, named DPTIP (IC50 = 30 nM). Although promising, DPTIP exhibits poor pharmacokinetics (PKs) with a low oral bioavailability (%F < 5), and a short half-life (t1/2 ≤ 0.5 h). To address these limitations, we previously developed DPTIP prodrugs by masking its phenolic hydroxyl group, demonstrating improved plasma exposure in mice. Recognizing that species-specific metabolic differences can influence prodrug PK, we expanded our studies to evaluate selected prodrugs in both mice and dogs. Methods: The scaleup of selected prodrugs was completed and two additional valine- ester based prodrugs were synthesized. Mice were dosed prodrugs via peroral route (10 mg/kg equivalent). For dog studies DPTIP was dosed via intravenous (1 mg/kg) or peroral route (2 mg/kg) and prodrugs were given peroral at a dose 2 mg/kg DPTIP equivalent. Plasma samples were collected at predetermined points and analyzed using developed LC/MS-MS methods. Results: In mice, several of the tested prodrugs showed similar or improved plasma exposures compared to DPTIP. However, in dog studies, the double valine ester prodrug 9, showed significant improvement with an almost two-fold increase in DPTIP plasma exposure (AUC0–t = 1352 vs. 701 pmol·h/mL), enhancing oral bioavailability from 8.9% to 17.3%. Conclusions: These findings identify prodrug 9 as a promising candidate for further evaluation and underscore the critical role of species-specific differences in prodrug PKs. Full article
(This article belongs to the Special Issue Prodrugs and Molecular Hybrids as Innovative Strategies in Medicinal Chemistry)
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14 pages, 1795 KiB  
Article
N-Succinylaspartic-Acid-Conjugated Riluzole Is a Safe and Potent Colon-Targeted Prodrug of Riluzole against DNBS-Induced Rat Colitis
by Jaejeong Kim, Changyu Kang, Jin-Wook Yoo, In-Soo Yoon and Yunjin Jung
Pharmaceutics 2023, 15(11), 2638; https://doi.org/10.3390/pharmaceutics15112638 - 16 Nov 2023
Cited by 2 | Viewed by 1586
Abstract
In our previous study, riluzole azo-linked to salicylic acid (RAS) was prepared as a colon-targeted prodrug of riluzole (RLZ) to facilitate the repositioning of RLZ as an anticolitic drug. RAS is more effective against rat colitis than RLZ and sulfasalazine, currently used as [...] Read more.
In our previous study, riluzole azo-linked to salicylic acid (RAS) was prepared as a colon-targeted prodrug of riluzole (RLZ) to facilitate the repositioning of RLZ as an anticolitic drug. RAS is more effective against rat colitis than RLZ and sulfasalazine, currently used as an anti-inflammatory bowel disease drug. The aim of this study is to further improve colon specificity, anticolitic potency, and safety of RAS. N-succinylaspart-1-ylRLZ (SAR) and N-succinylglutam-1-ylRLZ (SGR) were synthesized and evaluated as a “me-better” colon-targeted prodrug of RLZ against rat colitis. SAR but not SGR was converted to RLZ in the cecal contents, whereas both conjugates remained intact in the small intestine. When comparing the colon specificity of SAR with that of RAS, the distribution coefficient and cell permeability of SAR were lower than those of RAS. In parallel, oral SAR delivered a greater amount of RLZ to the cecum of rats than oral RAS. In a DNBS-induced rat model of colitis, oral SAR mitigated colonic damage and inflammation and was more potent than oral RAS. Moreover, upon oral administration, SAR had a greater ability to limit the systemic absorption of RLZ than RAS, indicating a reduced risk of systemic side effects of SAR. Taken together, SAR may be a “me-better” colon-targeted prodrug of RLZ to improve the safety and anticolitic potency of RAS, an azo-type colon-targeted prodrug of RLZ. Full article
(This article belongs to the Special Issue Prodrugs and Molecular Hybrids as Innovative Strategies in Medicinal Chemistry)
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Review

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51 pages, 16764 KiB  
Review
Synthesis of Arginase Inhibitors: An Overview
by Maria Cristina Molaro, Chiara Battisegola, Marica Erminia Schiano, Mariacristina Failla, Maria Grazia Rimoli, Loretta Lazzarato, Konstantin Chegaev and Federica Sodano
Pharmaceutics 2025, 17(1), 117; https://doi.org/10.3390/pharmaceutics17010117 - 16 Jan 2025
Cited by 1 | Viewed by 1142
Abstract
Arginase (ARG) is a binuclear manganese-containing metalloenzyme that can convert L-arginine to L-ornithine and urea and plays a key role in the urea cycle. It also mediates different cellular functions and processes such as proliferation, senescence, apoptosis, autophagy, and inflammatory responses in various [...] Read more.
Arginase (ARG) is a binuclear manganese-containing metalloenzyme that can convert L-arginine to L-ornithine and urea and plays a key role in the urea cycle. It also mediates different cellular functions and processes such as proliferation, senescence, apoptosis, autophagy, and inflammatory responses in various cell types. In mammals, there are two isoenzymes, ARG-1 and ARG-2; they are functionally similar, but their coding genes, tissue distribution, subcellular localization, and molecular regulation are distinct. In recent decades, the abnormal expression of ARG-1 or ARG-2 has been reported to be increasingly linked to a variety of diseases, including cardiovascular disease, inflammatory bowel disease, Alzheimer’s disease, and cancer. Therefore, considering the current relevance of this topic and the need to address the growing demand for new and more potent ARG inhibitors in the context of various diseases, this review was conceived. We will provide an overview of all classes of ARG inhibitors developed so far including compounds of synthetic, natural, and semisynthetic origin. For the first time, the synthesis protocol and optimized reaction conditions of each molecule, including those reported in patent applications, will be described. For each molecule, its inhibitory activity in terms of IC50 towards ARG-1 and ARG-2 will be reported specifying the type of assay conducted. Full article
(This article belongs to the Special Issue Prodrugs and Molecular Hybrids as Innovative Strategies in Medicinal Chemistry)
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54 pages, 14655 KiB  
Review
An Overview of the Structure–Activity Relationship in Novel Antimicrobial Thiazoles Clubbed with Various Heterocycles (2017–2023)
by Daniel Ungureanu, Brîndușa Tiperciuc, Cristina Nastasă, Ioana Ionuț, Gabriel Marc, Ilioara Oniga and Ovidiu Oniga
Pharmaceutics 2024, 16(1), 89; https://doi.org/10.3390/pharmaceutics16010089 - 9 Jan 2024
Cited by 9 | Viewed by 2737
Abstract
Antimicrobial resistance is an increasing problem for global public health. One of the strategies to combat this issue is the synthesis of novel antimicrobials through rational drug design based on extensive structure–activity relationship studies. The thiazole nucleus is a prominent feature in the [...] Read more.
Antimicrobial resistance is an increasing problem for global public health. One of the strategies to combat this issue is the synthesis of novel antimicrobials through rational drug design based on extensive structure–activity relationship studies. The thiazole nucleus is a prominent feature in the structure of many authorized antimicrobials, being clubbed with different heterocycles. The purpose of this review is to study the structure–activity relationship in antimicrobial thiazoles clubbed with various heterocycles, as reported in the literature between 2017 and 2023, in order to offer an overview of the last years in terms of antimicrobial research and provide a helpful instrument for future research in the field. Full article
(This article belongs to the Special Issue Prodrugs and Molecular Hybrids as Innovative Strategies in Medicinal Chemistry)
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