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New Strategies and Approaches in Polypharmacology
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New Strategies and Approaches in Polypharmacology

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

Deadline for manuscript submissions: closed (31 July 2024) | Viewed by 9845

Special Issue Editors

Dr. Sebastiano Intagliata

E-Mail Website
Guest Editor
Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Interests: medicinal chemistry; drug discovery; chemical synthesis; polypharmacology; multitarget ligands; anticancer agents; sigma receptor ligands; HO-1 inhibitors; 5-HT7 receptor ligands
Special Issues, Collections and Topics in MDPI journals
Dr. Agostino Marrazzo

E-Mail Website
Guest Editor
Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
Interests: sigma-1 receptor; sigma-2 receptor; opioid; chemical synthesis; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Almost twenty years ago polypharmacology has emerged as a new paradigm in drug discovery by overcoming the key concept of the “magic bullet” which dominated the medicinal chemistry scene for decades. Undoubtedly, the “one-molecule, one target” approach came up with successful blockbuster drugs which led to a significant increase in the quality of life. On the other hand, many of the current unmet medical needs are represented by multifactorial diseases, such as neurodegenerative and psychiatric disorders, metabolic diseases, infectious diseases, and cancer, which are caused by complex biochemical pathways dysregulation. In light of this, the combination of drugs (polypharmacy) is often essential to enhance therapeutic efficacy or delayed resistance development. Alternatively, polypharmacological agents (also known as multitarget-directed ligands or MTDLs), which are designed to act on multiple targets or disease pathways, offer a variety of advantages to overcome general issues associated with the co-administration of two or more agents. Unfortunately, the development of multitargeting compounds requires more complex and time-consuming steps than a “standard” drug. These phases include the identification of suitable target combinations, the multiple targeting ligand identification and optimization, and the validation of test systems to multitarget ligand characterization. As a result, the rational design of polypharmacology is highly challenging and still required new strategies and technologies to easily access novel drugs belonging to this class.

To that end, this Special Issue aims to collect original research, short communications, and review articles concerning advancements in the design and synthesis of novel polypharmacological agents, especially those that highlight new strategies and approaches are welcome. 

Dr. Sebastiano Intagliata
Dr. Agostino Marrazzo
Guest Editors

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 submissions that pass pre-check are 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. Molecules is an international peer-reviewed open access semimonthly 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 2700 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

  • polypharmacology
  • hybrid compounds
  • multitarget ligands
  • conjugate derivatives
  • drug design
  • drug development
  • chemical synthesis
  • multifactorial diseases
  • cancer
  • pain
  • neurodegenerative disorders
  • psychiatric disorders
  • metabolic diseases
  • infectious diseases

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Published Papers (4 papers)

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Research

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17 pages, 3082 KiB  
Article
Synthesis and Antioxidant Activities of Novel Pyrimidine Acrylamides as Inhibitors of Lipoxygenase: Molecular Modeling and In Silico Physicochemical Studies
by Michail Saragatsis and Eleni Pontiki
Molecules 2024, 29(6), 1189; https://doi.org/10.3390/molecules29061189 - 7 Mar 2024
Cited by 1 | Viewed by 1372
Abstract
The pyrimidine ring is present in various biomolecules such as DNA and RNA bases, aminoacids, vitamins, etc. Additionally, many clinically used drugs including methotrexate and risperidone contain the pyrimidine heterocyclic scaffold as well. Pyrimidine derivatives present diverse biological activities including antioxidant and anticancer [...] Read more.
The pyrimidine ring is present in various biomolecules such as DNA and RNA bases, aminoacids, vitamins, etc. Additionally, many clinically used drugs including methotrexate and risperidone contain the pyrimidine heterocyclic scaffold as well. Pyrimidine derivatives present diverse biological activities including antioxidant and anticancer activities and can be considered as privileged scaffolds in drug discovery for the treatment of various diseases. Piperidine pyrimidine amides have gained significant attention due to their enzymatic inhibitory activity. Based on our experience and ongoing investigation on cinnamic acid derivatives, their hybrids and substituted pteridines acting as lipoxygenase inhibitors, antioxidants, anti-cancer, and anti-inflammatory agents a series of novel piperidine pyrimidine cinnamic acids amides have been designed and synthesized. The novel hybrids were studied for their antioxidant and anti-inflammatory potential. They exhibit moderate antioxidant activity in the DPPH assay which may be related to their bulkiness. Moreover, moderate to good lipid peroxidation inhibition potential was measured. With regards to their lipoxygenase inhibitory activity, however, two highly potent inhibitors out of the nine tested derivatives were identified, demonstrating IC50 values of 10.7 μM and 1.1 μM, respectively. Molecular docking studies to the target enzyme lipoxygenase support the experimental results. Full article
(This article belongs to the Special Issue New Strategies and Approaches in Polypharmacology)
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27 pages, 3530 KiB  
Article
Targeting Hydroxybenzoic Acids to Mitochondria as a Strategy to Delay Skin Ageing: An In Vitro Approach
by Carlos Fernandes, Fernando Cagide, Jorge Simões, Carlos Pita, Eurico Pereira, Afonso J. C. Videira, Pedro Soares, José F. S. Duarte, António M. S. Santos, Paulo J. Oliveira, Fernanda Borges and Filomena S. G. Silva
Molecules 2022, 27(19), 6183; https://doi.org/10.3390/molecules27196183 - 21 Sep 2022
Cited by 3 | Viewed by 2407
Abstract
Targeting antioxidants to mitochondria is considered a promising strategy to prevent cellular senescence and skin ageing. In this study, we investigate whether four hydroxybenzoic acid-based mitochondria-targeted antioxidants (MitoBENs, MB1-4) could be used as potential active ingredients to prevent senescence in skin cells. Firstly, [...] Read more.
Targeting antioxidants to mitochondria is considered a promising strategy to prevent cellular senescence and skin ageing. In this study, we investigate whether four hydroxybenzoic acid-based mitochondria-targeted antioxidants (MitoBENs, MB1-4) could be used as potential active ingredients to prevent senescence in skin cells. Firstly, we evaluated the chemical stability, cytotoxicity, genotoxicity and mitochondrial toxicity of all compounds. We followed this by testing the antioxidant protective capacity of the two less toxic compounds on human skin fibroblasts. We then assessed the effects of the best hit on senescence, inflammation and mitochondrial remodeling on a 3D skin cell model, while also testing its mutagenic potential. Cytotoxicity and mitochondrial toxicity rankings were produced: MB3 < MB4 ≃ MB1 < MB2 and MB3 < MB1 < MB4 < MB2, respectively. These results suggest that pyrogallol-based compounds (MB2 and MB4) have lower cytotoxicity. The pyrogallol derivative, MB2, containing a 6-carbon spacer, showed a more potent antioxidant protective activity against hydrogen peroxide cytotoxicity. In a 3D skin cell model, MB2 also decreased transcripts related to senescence. In sum, MB2’s biological safety profile, good chemical stability and lack of mutagenicity, combined with its anti-senescence effect, converts MB2 into a good candidate for further development as an active ingredient for skin anti-ageing products. Full article
(This article belongs to the Special Issue New Strategies and Approaches in Polypharmacology)
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27 pages, 7958 KiB  
Article
Oncolytic Newcastle Disease Virus Co-Delivered with Modified PLGA Nanoparticles Encapsulating Temozolomide against Glioblastoma Cells: Developing an Effective Treatment Strategy
by Zahraa A. Kadhim, Ghassan M. Sulaiman, Ahmed M. Al-Shammari, Riaz A. Khan, Osamah Al Rugaie and Hamdoon A. Mohammed
Molecules 2022, 27(18), 5757; https://doi.org/10.3390/molecules27185757 - 6 Sep 2022
Cited by 16 | Viewed by 3319
Abstract
Glioblastoma multiforme (GBM) is considered to be one of the most serious version of primary malignant tumors. Temozolomide (TMZ), an anti-cancer drug, is the most common chemotherapeutic agent used for patients suffering from GBM. However, due to its inherent instability, short biological half-life, [...] Read more.
Glioblastoma multiforme (GBM) is considered to be one of the most serious version of primary malignant tumors. Temozolomide (TMZ), an anti-cancer drug, is the most common chemotherapeutic agent used for patients suffering from GBM. However, due to its inherent instability, short biological half-life, and dose-limiting characteristics, alternatives to TMZ have been sought. In this study, the TMZ-loaded PLGA nanoparticles were prepared by employing the emulsion solvent evaporation technique. The prepared TMZ-PLGA-NPs were characterized using FT-IR, zeta potential analyses, XRD pattern, particle size estimation, TEM, and FE-SEM observations. The virotherapy, being safe, selective, and effective in combating cancer, was employed, and TMZ-PLGA-NPs and oncolytic Newcastle Disease Virus (NDV) were co-administered for the purpose. An AMHA1-attenuated strain of NDV was propagated in chicken embryos, and the virus was titrated in Vero-slammed cells to determine the infective dose. The in vitro cytotoxic effects of the TMZ, NDV, and the TMZ-PLGA-NPs against the human glioblastoma cancer cell line, AMGM5, and the normal cell line of rat embryo fibroblasts (REFs) were evaluated. The synergistic effects of the nano-formulation and viral strain combined therapy was observed on the cell lines in MTT viability assays, together with the Chou–Talalay tests. The outcomes of the in vitro investigation revealed that the drug combinations of NDV and TMZ, as well as NDV and TMZ-PLGA-NPs exerted the synergistic enhancements of the antitumor activity on the AMGM5 cell lines. The effectiveness of both the mono, and combined treatments on the capability of AMGM5 cells to form colonies were also examined with crystal violet dyeing tests. The morphological features, and apoptotic reactions of the treated cells were investigated by utilizing the phase-contrast inverted microscopic examinations, and acridine orange/propidium iodide double-staining tests. Based on the current findings, the potential for the use of TMZ and NDV as part of a combination treatment of GBM is significant, and may work for patients suffering from GBM. Full article
(This article belongs to the Special Issue New Strategies and Approaches in Polypharmacology)
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Review

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23 pages, 8620 KiB  
Review
Chlorambucil-Bearing Hybrid Molecules in the Development of Potential Anticancer Agents
by Sijongesonke Peter and Blessing Atim Aderibigbe
Molecules 2023, 28(19), 6889; https://doi.org/10.3390/molecules28196889 - 30 Sep 2023
Cited by 3 | Viewed by 1694
Abstract
Increasing cases of cancer have been a primary concern in recent decades. Developing new chemotherapeutics is challenging and has been faced with limitations, such as multidrug resistance, poor specificity, selectivity, and toxicity. The aforementioned factors contribute to treatment failure. Hybrid compounds have features [...] Read more.
Increasing cases of cancer have been a primary concern in recent decades. Developing new chemotherapeutics is challenging and has been faced with limitations, such as multidrug resistance, poor specificity, selectivity, and toxicity. The aforementioned factors contribute to treatment failure. Hybrid compounds have features that can overcome the limitations mentioned above. Chlorambucil, an anticancer drug that is used to treat prostate and breast cancer, suffers from poor aqueous solubility and specificity, a short half-life, and severe side effects, including anaemia and bone marrow suppression. It compromises the immune system, resulting in treatment failure. Hence, its combination with other pharmacophores has been reported to result in effective anticancer agents with fewer side effects and high therapeutic outcomes. Furthermore, this review gives an update (2010 to date) on the developments of chlorambucil hybrid compounds with anticancer activity, and the structure-activity relationship (SAR), and also highlights future strategies for developing novel anticancer agents. Full article
(This article belongs to the Special Issue New Strategies and Approaches in Polypharmacology)
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