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Prodrugs and Their Future Prospects and Clinical Impact

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 33364

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Special Issue Editor

Prof. Dr. Rafik Karaman

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Guest Editor

1. Pharmaceutical & Medicinal Chemistry Department, Faculty of Pharmacy, Al-Quds University, Jerusalem P.O. Box 20002, Palestine
2. Department of Sciences, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
Interests: design and synthesis of anticancer prodrugs with targeting properties determined by the linker’s type; design and synthesis of prodrugs with inefficient bioavailability; design and synthesis of prodrugs for masking the bitter sensation of commonly used drugs
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Special Issue Information

Dear Colleagues,

Prodrugs are pharmacologically inactive compounds which, upon exposure to the physiological environment, undergo bioactivation to release the active parent drug and a non-toxic moiety. The prodrug concept was invented to overcome biopharmaceutical problems from which several commonly used drugs suffer, such as poor oral bioavailability, poor tolerability due to side effects, bitter taste, and short duration of action. Prodrugs can be activated through chemical or enzymatic reactions.
The prodrug concept has reached a great success in the last few years. It is estimated that about 10% of all marketed drugs are prodrugs, 20% of small drugs approved between 2000 and 2008 were prodrugs, and the percentage of prodrugs in the drug market between 2008 and 2017 was 12%. The prodrug concept has many advantages over the conventional drug design strategies and has the potential to be quite an efficient approach for the treatment of current and future diseases.
In this Special Issue, the various strategies employed in the prodrug approach along with several selected successful prodrugs will be reported. Reviews and original research contributions are expected on, but not limited to, prodrugs for the treatment of cardiovascular system, central nervous system, gastrointestinal tract, immune system dysfunctions, as well as on those used in ophthalmology and oncology. In addition, reports on successful antiviral, antibacterial, antifungal, antiprotozoal, and other miscellaneous prodrugs are encouraged.

Prof. Dr. Rafik Karaman
Guest Editor

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Keywords

Prodrugs Design
Targeted Prodrugs
Enhancing the Bioavailability of Drugs

Published Papers (6 papers)

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Research

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11 pages, 1884 KiB

Open AccessArticle

Novel Cationic Prodrug of Ubiquinol-10 Enhances Intestinal Absorption via Efficient Formation of Nanosized Mixed-Micelles with Bile Acid Anions

by Shuichi Setoguchi, Ryoji Hidaka, Nami Nagata-Akaho, Daisuke Watase, Mitsuhisa Koga, Kazuhisa Matsunaga, Yoshiharu Karube and Jiro Takata

Molecules 2020, 25(3), 546; https://doi.org/10.3390/molecules25030546 - 27 Jan 2020

Cited by 5 | Viewed by 2437

Abstract

The aim of this study was to develop a prodrug of ubiquinol-10 (UqH-10), the active form of ubiquinone-10 (Uq-10), for oral delivery. Bioavailability of UqH-10 is hampered by its high susceptibility to oxidation and water-insolubility. We prepared three novel N,N-dimethylglycine ester derivatives of UqH-10, including a 1-monoester (UqH-1-DMG), 4-monoester (UqH-4-DMG), and 1,4-bis-ester (UqH-DMG), and assessed their physicochemical properties in vitro and in vivo. UqH-DMG spontaneously formed an aqueous micelle solution comprising 20 nm particles at 36.5 °C. Cationic UqH-DMG formed nano-sized (5 nm) mixed-micelles with taurocholic acid. Reconversion of the derivatives to UqH-10 was accelerated in human liver microsomes. The oral bioavailability of UqH-10 after administration of UqH-derivatives or Uq-10 was determined in fasted and postprandial rats secreting normal and high levels of bile, respectively. In fasted rats, plasma UqH-10 after UqH-derivatives administration reached C_max at 2–3 h and after Uq-10 administration, it remained low. The AUC_0-24h of UqH-10 after UqH-derivatives administration was 2–3-fold higher than that after Uq-10 administration. In postprandial rats, the T_max of UqH-10 after UqH-derivatives administration was an hour earlier than after Uq-10 administration. In conclusion, cationic UqH-derivatives are convenient prodrugs that enhance UqH-10 bioavailability by forming nanosized mixed-micelles with intestinal bile acids. Full article

(This article belongs to the Special Issue Prodrugs and Their Future Prospects and Clinical Impact)

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10 pages, 1703 KiB

Open AccessArticle

Antiproliferative Aspect of Benzimidazole Derivatives’ Activity and Their Impact on NF-κB Expression

by Katarzyna Błaszczak-Świątkiewicz

Molecules 2019, 24(21), 3902; https://doi.org/10.3390/molecules24213902 - 29 Oct 2019

Cited by 9 | Viewed by 2236

Abstract

Benzimidazoles belong to a new class of bioreductive agents with cytotoxic activity towards solid tumor cells, especially in their first stage of growth, which is characterized by low oxygen concentration. Bioreductive agents represent a class of prodrugs that target hypoxic tumor cells. Their bioactivity depends on the reactivity of their functional chemical groups. Their efficacy requires metabolic reduction and subsequent generation of toxic prodrugs. Chemoresistance of tumor cells is a major problem for successful antitumor therapy for many types of tumors, especially for breast cancer. The present study was performed to assess the effect of the antiproliferation activity of the tested benzimidazoles by way of NF-κB expression inhibition. The activity of the tested compounds on T47D and MCF7 cells was examined by WST, western blot, NF-κB transactivation assay, and apoptotic cell population analysis. Compound 3 was highly cytotoxically active against T47D cells, especially in hypoxic conditions. Its IC₅₀ of 0.31 ± 0.06 nM, although weaker than tirapazamine, was significantly higher than the other tested compounds (2.4–3.0 fold). The increased bax protein expression upon exposure to the tested compounds indicated intercellular apoptotic pathway activity, with tumor cell death by way of apoptosis. Increased bax protein synthesis and apoptotic cell dominance upon treatment, especially with N-oxide derivatives (92% apoptotic cells among T47D cell populations during treatment with compound 3), were correlated with each other. Additionally, both increased bax protein and decreased NF-κB protein expression supported antiproliferative activity via NF-κB–DNA binding inhibition associated with the tested compounds. Compound 3 appeared to be the strongest inhibitor of NF-κB expression in hypoxic conditions (the potency against NF-κB expression was about 75% of that of tirapazamine). The present studies involving this class of heterocyclic small molecules proved their potential usefulness in anticancer therapy as compounds be able to limit tumor cell proliferation and reverse drug resistance by NF-κB repression. Full article

(This article belongs to the Special Issue Prodrugs and Their Future Prospects and Clinical Impact)

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13 pages, 2420 KiB

Open AccessArticle

Evaluation of Elastin-Like Polypeptides for Tumor Targeted Delivery of Doxorubicin to Glioblastoma

by Sonja Dragojevic, Rebecca Mackey and Drazen Raucher

Molecules 2019, 24(18), 3242; https://doi.org/10.3390/molecules24183242 - 6 Sep 2019

Cited by 14 | Viewed by 4139

Abstract

To increase treatment efficiency for glioblastoma, we have developed a system to selectively deliver chemotherapeutic doxorubicin (Dox) to Glioblastoma (GBM) tumors. This carrier is based on elastin-like polypeptide (ELP), which is soluble at physiological temperatures but undergoes a phase transition and accumulates at tumor sites with externally applied, mild (40–41 °C) hyperthermia. The CPP-ELP-Dox conjugate consists of a cell penetrating peptide (CPP), which facilitates transcytosis through the blood brain barrier and cell entry, and a 6-maleimidocaproyl hydrazone derivative of doxorubicin at the C-terminus of ELP. The acid-sensitive hydrazone linker ensures release of Dox in the lysosomes/endosomes after cellular uptake of the drug conjugate. We have shown that CPP-ELP-Dox effectively inhibits cell proliferation in three GBM cell lines. Both the free drug and CPP-ELP-Dox conjugate exhibited similar in vitro cytotoxicity, although their subcellular localization was considerably different. The Dox conjugate was mainly dispersed in the cytoplasm, while free drug had partial nuclear accumulation in addition to cytoplasmic distribution. The intracellular Dox concentration was increased in the CPP-ELP-Dox cells compared to that in the cells treated with free Dox, which positively correlates with cytotoxic activity. In summary, our findings demonstrate that CPP-ELP-Dox effectively kills GBM cells. Development of such a drug carrier has the potential to greatly improve current therapeutic approaches for GBM by increasing the specificity and efficacy of treatment and reducing cytotoxicity in normal tissues. Full article

(This article belongs to the Special Issue Prodrugs and Their Future Prospects and Clinical Impact)

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20 pages, 3290 KiB

Open AccessArticle

Antiplasmodial Activity and In Vivo Bio-Distribution of Chloroquine Molecules Released with a 4-(4-Ethynylphenyl)-Triazole Moiety from Organometallo-Cobalamins

by Jeremie Rossier, Sara Nasiri Sovari, Aleksandar Pavic, Sandra Vojnovic, Tameryn Stringer, Sarah Bättig, Gregory S. Smith, Jasmina Nikodinovic-Runic and Fabio Zobi

Molecules 2019, 24(12), 2310; https://doi.org/10.3390/molecules24122310 - 21 Jun 2019

Cited by 16 | Viewed by 3999

Abstract

We have explored the possibility of using organometallic derivatives of cobalamin as a scaffold for the delivery of the same antimalarial drug to both erythro- and hepatocytes. This hybrid molecule approach, intended as a possible tool for the development of multi-stage antimalarial agents, pivots on the preparation of azide-functionalized drugs which, after coupling to the vitamin, are released with a 4-(4-ethynylphenyl)-triazole functionality. Three chloroquine and one imidazolopiperazine derivative (based on the KAF156 structure) were selected as model drugs. One hybrid chloroquine conjugate was extensively studied via fluorescent labelling for in vitro and in vivo bio-distribution studies and gave proof-of-concept for the design. It showed no toxicity in vivo (zebrafish model) as well as no hepatotoxicity, no cardiotoxicity or developmental toxicity of the embryos. All 4-(4-ethynylphenyl)-triazole derivatives of chloroquine were equally active against chloroquine-resistant (CQR) and chloroquine-sensitive (CQS) Plasmodium falciparum strains. Full article

(This article belongs to the Special Issue Prodrugs and Their Future Prospects and Clinical Impact)

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Review

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16 pages, 1564 KiB

Open AccessReview

Antibacterial Prodrugs to Overcome Bacterial Resistance

by Buthaina Jubeh, Zeinab Breijyeh and Rafik Karaman

Molecules 2020, 25(7), 1543; https://doi.org/10.3390/molecules25071543 - 28 Mar 2020

Cited by 56 | Viewed by 10383

Abstract

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. Full article

(This article belongs to the Special Issue Prodrugs and Their Future Prospects and Clinical Impact)

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18 pages, 2506 KiB

Open AccessReview

Newly Developed Prodrugs and Prodrugs in Development; an Insight of the Recent Years

by Anas Najjar, Abderrahman Najjar and Rafik Karaman

Molecules 2020, 25(4), 884; https://doi.org/10.3390/molecules25040884 - 17 Feb 2020

Cited by 39 | Viewed by 9465

Abstract

Background: The design and development of prodrugs is the most common and effective strategy to overcome pharmacokinetic and pharmacodynamic drawbacks of active drugs. A respected number of prodrugs have been reached the drugs market throughout history and the recent years have witnessed a significant increase in the use of prodrugs as a replacement of their parent drugs for an efficient treatment of various ailment. Methods: A Scan conducted to find recent approved prodrugs and prodrugs in development. Results: Selected prodrugs were reported and categorized in accordance to their target systems. Conclusions: the prodrug approach has shown many successes and still remains a viable and effective approach to deliver new active agents. This conclusion is supported by the recent approved prodrugs and the scan of clinical trials conducted between 2013–2018. Full article

(This article belongs to the Special Issue Prodrugs and Their Future Prospects and Clinical Impact)

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