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Special Issue "Old Pharmaceuticals with New Applications"

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: 31 December 2019

Special Issue Editor

Guest Editor
Prof. Dr. Maria Emília de Sousa

1. Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências, Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal
2. Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, S/N 4450-208 Matosinhos, Portugal
Website | E-Mail
Interests: medicinal chemistry; organic synthesis; heterocycles, P-glycoprotein; anticancer; anticoagulants; chiral drugs; marine natural products

Special Issue Information

Dear Colleagues,

The decline or leveling out of output of the R&D programs from pharmaceutical companies may have begun to turn a corner compared to the early years of the 21st century. Although one reason for this increase is immunopharmacology-based treatments, small molecules still play an important role. Medicinal chemistry approaches to find small molecule lead compounds with the desired pharmacological activity continue to use natural products, synthesis, and existing drugs as sources.

In recent years, we have experienced a surge of interest in drug repositioning. There is a trend in finding new uses for existing drugs, especially in diseases where there is an unmet clinical need such as neglected and orphan diseases. Another opportunity is developing novel applications using a combination of old drugs.

The most fruitful basis for the discovery of a new drug is to start with an old drug” goes a famous statement from Sir James Black, which has received many adherents this century, not only in finding new applications but also looking for the unexploited potential of old drugs as starting points for molecular modifications.

The journal Pharmaceuticals invites both reviews and original articles shedding light on the challenges and opportunities of using old pharmaceuticals in drug discovery. Topics include: drug repositioning, selective optimization of side effects, drug metabolites as sources of new drugs, old drug combinations, beyond pharmaceuticals applications. The collection of manuscripts will be published as a Special Issue of the journal.

Dr. Maria Emília de Sousa
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Pharmaceuticals is an international peer-reviewed open access quarterly 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 850 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

  • drug repositioning
  • drug discovery
  • old drugs
  • sosa
  • drug metabolism
  • drug combinations

Published Papers (7 papers)

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Research

Jump to: Review

Open AccessArticle Proximal Pathway Enrichment Analysis for Targeting Comorbid Diseases via Network Endopharmacology
Pharmaceuticals 2018, 11(3), 61; https://doi.org/10.3390/ph11030061
Received: 30 April 2018 / Revised: 15 June 2018 / Accepted: 19 June 2018 / Published: 22 June 2018
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Abstract
The past decades have witnessed a paradigm shift from the traditional drug discovery shaped around the idea of “one target, one disease” to polypharmacology (multiple targets, one disease). Given the lack of clear-cut boundaries across disease (endo)phenotypes and genetic heterogeneity across patients, a
[...] Read more.
The past decades have witnessed a paradigm shift from the traditional drug discovery shaped around the idea of “one target, one disease” to polypharmacology (multiple targets, one disease). Given the lack of clear-cut boundaries across disease (endo)phenotypes and genetic heterogeneity across patients, a natural extension to the current polypharmacology paradigm is to target common biological pathways involved in diseases via endopharmacology (multiple targets, multiple diseases). In this study, we present proximal pathway enrichment analysis (PxEA) for pinpointing drugs that target common disease pathways towards network endopharmacology. PxEA uses the topology information of the network of interactions between disease genes, pathway genes, drug targets and other proteins to rank drugs by their interactome-based proximity to pathways shared across multiple diseases, providing unprecedented drug repurposing opportunities. Using PxEA, we show that many drugs indicated for autoimmune disorders are not necessarily specific to the condition of interest, but rather target the common biological pathways across these diseases. Finally, we provide high scoring drug repurposing candidates that can target common mechanisms involved in type 2 diabetes and Alzheimer’s disease, two conditions that have recently gained attention due to the increased comorbidity among patients. Full article
(This article belongs to the Special Issue Old Pharmaceuticals with New Applications)
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Graphical abstract

Open AccessArticle Mitoxantrone is More Toxic than Doxorubicin in SH-SY5Y Human Cells: A ‘Chemobrain’ In Vitro Study
Pharmaceuticals 2018, 11(2), 41; https://doi.org/10.3390/ph11020041
Received: 8 March 2018 / Revised: 28 April 2018 / Accepted: 29 April 2018 / Published: 5 May 2018
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Abstract
The potential neurotoxic effects of anticancer drugs, like doxorubicin (DOX) and mitoxantrone (MTX; also used in multiple sclerosis), are presently important reasons for concern, following epidemiological data indicating that cancer survivors submitted to chemotherapy may suffer cognitive deficits. We evaluated the in vitro
[...] Read more.
The potential neurotoxic effects of anticancer drugs, like doxorubicin (DOX) and mitoxantrone (MTX; also used in multiple sclerosis), are presently important reasons for concern, following epidemiological data indicating that cancer survivors submitted to chemotherapy may suffer cognitive deficits. We evaluated the in vitro neurotoxicity of two commonly used chemotherapeutic drugs, DOX and MTX, and study their underlying mechanisms in the SH-SY5Y human neuronal cell model. Undifferentiated human SH-SY5Y cells were exposed to DOX or MTX (0.13, 0.2 and 0.5 μM) for 48 h and two cytotoxicity assays were performed, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) reduction and the neutral red (NR) incorporation assays. Phase contrast microphotographs, Hoechst, and acridine orange/ethidium bromide stains were performed. Mitochondrial membrane potential was also assessed. Moreover, putative protective drugs, namely the antioxidants N-acetyl-l-cysteine (NAC; 1 mM) and 100 μM tiron, the inhibitor of caspase-3/7, Ac-DEVD-CHO (100 μM), and a protein synthesis inhibitor, cycloheximide (CHX; 10 nM), were tested to prevent DOX- or MTX-induced toxicity. The MTT reduction assay was also done in differentiated SH-SY5Y cells following exposure to 0.2 μM DOX or MTX. MTX was more toxic than DOX in both cytotoxicity assays and according to the morphological analyses. MTX also evoked a higher number of apoptotic nuclei than DOX. Both drugs, at the 0.13 μM concentration, caused mitochondrial membrane potential depolarization after a 48-h exposure. Regarding the putative neuroprotectors, 1 mM NAC was not able to prevent the cytotoxicity caused by either drug. Notwithstanding, 100 μM tiron was capable of partially reverting MTX-induced cytotoxicity in the NR uptake assay. One hundred μM Ac-DEVD-CHO and 10 nM cycloheximide (CHX) also partially prevented the toxicity induced by DOX in the NR uptake assay. MTX was more toxic than DOX in differentiated SH-SY5Y cells, while MTX had similar toxicity in differentiated and undifferentiated SH-SY5Y cells. In fact, MTX was the most neurotoxic drug tested and the mechanisms involved seem dissimilar among drugs. Thus, its toxicity mechanisms need to be further investigated as to determine the putative neurotoxicity for multiple sclerosis and cancer patients. Full article
(This article belongs to the Special Issue Old Pharmaceuticals with New Applications)
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Open AccessArticle A Novel Interaction Between the TLR7 and a Colchicine Derivative Revealed Through a Computational and Experimental Study
Pharmaceuticals 2018, 11(1), 22; https://doi.org/10.3390/ph11010022
Received: 17 January 2018 / Revised: 1 February 2018 / Accepted: 13 February 2018 / Published: 16 February 2018
PDF Full-text (9398 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The Toll-Like Receptor 7 (TLR7) is an endosomal membrane receptor involved in the innate immune system response. Its best-known small molecule activators are imidazoquinoline derivatives such as imiquimod (R-837) and resiquimod (R-848). Recently, an interaction between R-837 and the colchicine binding site of
[...] Read more.
The Toll-Like Receptor 7 (TLR7) is an endosomal membrane receptor involved in the innate immune system response. Its best-known small molecule activators are imidazoquinoline derivatives such as imiquimod (R-837) and resiquimod (R-848). Recently, an interaction between R-837 and the colchicine binding site of tubulin was reported. To investigate the possibility of an interaction between structural analogues of colchicine and the TLR7, a recent computational model for the dimeric form of the TLR7 receptor was used to determine a possible interaction with a colchicine derivative called CR42-24, active as a tubulin polymerization inhibitor. The estimated values of the binding energy of this molecule with respect to the TLR7 receptor were comparable to the energies of known binders as reported in a previous study. The binding to the TLR7 was further assessed by introducing genetic transformations in the TLR7 gene in cancer cell lines and exposing them to the compound. A negative shift of the IC50 value in terms of cell growth was observed in cell lines carrying the mutated TLR7 gene. The reported study suggests a possible interaction between TLR7 and a colchicine derivative, which can be explored for rational design of new drugs acting on this receptor by using a colchicine scaffold for additional modifications. Full article
(This article belongs to the Special Issue Old Pharmaceuticals with New Applications)
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Open AccessArticle A Triphenylphosphonium-Functionalized Mitochondriotropic Nanocarrier for Efficient Co-Delivery of Doxorubicin and Chloroquine and Enhanced Antineoplastic Activity
Pharmaceuticals 2017, 10(4), 91; https://doi.org/10.3390/ph10040091
Received: 24 October 2017 / Revised: 14 November 2017 / Accepted: 18 November 2017 / Published: 21 November 2017
Cited by 1 | PDF Full-text (3537 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Drug delivery systems that target subcellular organelles and, in particular, mitochondria are considered to have great potential in treating disorders that are associated with mitochondrial dysfunction, including cancer or neurodegenerative diseases. To this end, a novel hyperbranched mitochondriotropic nanocarrier was developed for the
[...] Read more.
Drug delivery systems that target subcellular organelles and, in particular, mitochondria are considered to have great potential in treating disorders that are associated with mitochondrial dysfunction, including cancer or neurodegenerative diseases. To this end, a novel hyperbranched mitochondriotropic nanocarrier was developed for the efficient co-delivery of two different (both in chemical and pharmacological terms) bioactive compounds. The carrier is based on hyperbranched poly(ethyleneimine) functionalized with triphenylphosphonium groups that forms ~100 nm diameter nanoparticles in aqueous media and can encapsulate doxorubicin (DOX), a well-known anti-cancer drug, and chloroquine (CQ), a known chemosensitizer with arising potential in anticancer medication. The anticancer activity of this system against two aggressive DOX-resistant human prostate adenocarcinoma cell lines and in in vivo animal studies was assessed. The co-administration of encapsulated DOX and CQ leads to improved cell proliferation inhibition at extremely low DOX concentrations (0.25 μΜ). In vivo experiments against DU145 human prostate cancer cells grafted on immunodeficient mice resulted in tumor growth arrest during the three-week administration period and no pervasive side effects. The findings put forward the potential of such targeted low dose combination treatments as a therapeutic scheme with minimal adverse effects. Full article
(This article belongs to the Special Issue Old Pharmaceuticals with New Applications)
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Review

Jump to: Research

Open AccessReview Changing Trends in Computational Drug Repositioning
Pharmaceuticals 2018, 11(2), 57; https://doi.org/10.3390/ph11020057
Received: 30 April 2018 / Revised: 1 June 2018 / Accepted: 2 June 2018 / Published: 5 June 2018
Cited by 5 | PDF Full-text (288 KB) | HTML Full-text | XML Full-text
Abstract
Efforts to maximize the indications potential and revenue from drugs that are already marketed are largely motivated by what Sir James Black, a Nobel Prize-winning pharmacologist advocated—“The most fruitful basis for the discovery of a new drug is to start with an old
[...] Read more.
Efforts to maximize the indications potential and revenue from drugs that are already marketed are largely motivated by what Sir James Black, a Nobel Prize-winning pharmacologist advocated—“The most fruitful basis for the discovery of a new drug is to start with an old drug”. However, rational design of drug mixtures poses formidable challenges because of the lack of or limited information about in vivo cell regulation, mechanisms of genetic pathway activation, and in vivo pathway interactions. Hence, most of the successfully repositioned drugs are the result of “serendipity”, discovered during late phase clinical studies of unexpected but beneficial findings. The connections between drug candidates and their potential adverse drug reactions or new applications are often difficult to foresee because the underlying mechanism associating them is largely unknown, complex, or dispersed and buried in silos of information. Discovery of such multi-domain pharmacomodules—pharmacologically relevant sub-networks of biomolecules and/or pathways—from collection of databases by independent/simultaneous mining of multiple datasets is an active area of research. Here, while presenting some of the promising bioinformatics approaches and pipelines, we summarize and discuss the current and evolving landscape of computational drug repositioning. Full article
(This article belongs to the Special Issue Old Pharmaceuticals with New Applications)
Open AccessReview Old Drugs as New Treatments for Neurodegenerative Diseases
Pharmaceuticals 2018, 11(2), 44; https://doi.org/10.3390/ph11020044
Received: 27 April 2018 / Revised: 7 May 2018 / Accepted: 8 May 2018 / Published: 11 May 2018
Cited by 3 | PDF Full-text (3114 KB) | HTML Full-text | XML Full-text
Abstract
Neurodegenerative diseases are increasing in number, given that the general global population is becoming older. They manifest themselves through mechanisms that are not fully understood, in many cases, and impair memory, cognition and movement. Currently, no neurodegenerative disease is curable, and the treatments
[...] Read more.
Neurodegenerative diseases are increasing in number, given that the general global population is becoming older. They manifest themselves through mechanisms that are not fully understood, in many cases, and impair memory, cognition and movement. Currently, no neurodegenerative disease is curable, and the treatments available only manage the symptoms or halt the progression of the disease. Therefore, there is an urgent need for new treatments for this kind of disease, since the World Health Organization has predicted that neurodegenerative diseases affecting motor function will become the second-most prevalent cause of death in the next 20 years. New therapies can come from three main sources: synthesis, natural products, and existing drugs. This last source is known as drug repurposing, which is the most advantageous, since the drug’s pharmacokinetic and pharmacodynamic profiles are already established, and the investment put into this strategy is not as significant as for the classic development of new drugs. There have been several studies on the potential of old drugs for the most relevant neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis. Full article
(This article belongs to the Special Issue Old Pharmaceuticals with New Applications)
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Graphical abstract

Open AccessReview Drug Repurposing for Schistosomiasis: Combinations of Drugs or Biomolecules
Pharmaceuticals 2018, 11(1), 15; https://doi.org/10.3390/ph11010015
Received: 25 October 2017 / Revised: 19 January 2018 / Accepted: 31 January 2018 / Published: 5 February 2018
Cited by 3 | PDF Full-text (4659 KB) | HTML Full-text | XML Full-text
Abstract
Schistosomiasis is a major neglected tropical disease. Control of schistosomiasis currently relies on a single drug, praziquantel, and despite its efficacy against the all schistosome species that parasitize humans, it displays some problematic drawbacks and alone is ineffective in counteracting adverse pathologies associated
[...] Read more.
Schistosomiasis is a major neglected tropical disease. Control of schistosomiasis currently relies on a single drug, praziquantel, and despite its efficacy against the all schistosome species that parasitize humans, it displays some problematic drawbacks and alone is ineffective in counteracting adverse pathologies associated with infection. Moreover, due to the development of the potential emergence of PZQ-resistant strains, the search for additional or alternative antischistosomal drugs have become a public health priority. The current drug discovery for schistosomiasis has been slow and uninspiring. By contrast, repurposing of existing approved drugs may offer a safe, rapid and cost-effective alternative. Combined treatment with PZQ and other drugs with different mode of action, i.e., antimalarials, shows promise results. In addition, a combination of anthelminthic drugs with antioxidant might be advantageous for modulating oxidative processes associated with schistosomiasis. Herein, we review studies dealing with combination therapies that involve PZQ and other anthelminthic drugs and/or antioxidant agents in treatment of schistosomiasis. Whereas PZQ combined with antioxidant agents might or might not interfere with anthelminthic efficacy, combinations may nonetheless ameliorate tissue damage and infection-associated complications. In fact, alone or combine with other drugs, antioxidants might be a valuable adjuvant to reduce morbidity and mortality of schistosomiasis. Therefore, attempting new combinations of anthelmintic drugs with other biomolecules such as antioxidants provides new avenues for discovery of alternatives to PZQ. Full article
(This article belongs to the Special Issue Old Pharmaceuticals with New Applications)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Fast tracking antimalarial drug discovery through drug repositioning
Article Type: Review
Authors: Niroshini Nirmalan
Affiliation: Environment and Life sciences, University of Salford, Greater Manchester, UK

Title: New potential of the re-purposed drugs in solid cancers.
Article type: Review
Author: Patrycja Nowak-Sliwinska
Affiliation: School of Pharmaceutical Sciences, University of Geneva

Title: A Novel Interaction Between the TLR7 and a Colchicine Derivative Revealed Through a Computational and Experimental Study
Article type: Article
Author: Francesco Gentile 1, Marco A. Deriu 2,3, Khaled H. Barakat 4, Andrea Danani 3 and Jack A. Tuszynski 1,5
Affiliation:
1. Department of Physics, University of Alberta, Edmonton, AB, Canada
2. Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Torino, Italy
3. Istituto Dalle Molle di studi sull’Intelligenza Artificiale (IDSIA), Scuola universitaria professionale della Svizzera italiana (SUPSI), Università della Svizzera italiana (USI), Manno, Switzerland
4. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
5. Department of Oncology, University of Alberta, Edmonton, AB, Canada
Abstract: The Toll-Like Receptor 7 (TLR7) is an endosomal membrane receptor involved in the innate immune system response. Its best-known small molecule activators are imidazoquinoline derivatives such as Imiquimod and Resiquimod, and adenine analogues. A recent computational model for the dimeric form of the receptor was used to determine a possible interaction with a colchicine derivative, active as a tubulin polymerization inhibitor. The estimated values of the binding energy of this molecule with respect to the TLR7 receptor was comparable with the energies of known binders as reported in a previous study. The binding to the TLR7 was further assessed by introducing genetic transformations in the TLR7 gene in cancer cell lines and exposing them to the compound. A negative shift of the IC50 value in terms of cell growth was observed in cell lines carrying the mutated TLR7 gene. The reported study suggests a possible interaction between TLR7 and a colchicine derivative, which can be explored for rational design of new drugs acting on this receptor by using a colchicine scaffold for additional modifications.

Title: Targeting DNA repair with repurposed drugs in resistant cancers
Article Type: Opinion
Authors: Panagiotis J. Vlachostergios
Affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA

Title: A triphenylphosphonium-functionalized mitochondriotropic nanocarrier for efficient co-delivery of doxorubicin and chloroquine and enhanced antineoplastic activity
Article type: Article
Author: Katerina N Panagiotaki; Zili Sideratou; Spiros A Vlahopoulos; Maria Paravatou-Petsotas; Michael Zachariadis; Nikolas Khoury; Vassilis Zoumpourlis; Dimitris Tsiourvas *
Affiliation: NCSR “Demokritos”, Institute of Nanosciences and Nanotechnology, 15310 Aghia Paraskevi, Attiki, Greece

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