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Special Issue "Medicinal Chemistry in Europe"

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

Deadline for manuscript submissions: 31 January 2019

Special Issue Editor

Guest Editor
Prof. Dr. Silvia Schenone *

Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy
Website | E-Mail
Interests: protein kinase inhibitors; anticancer agents; heterocyclic chemistry; drug delivery systems; prodrug formulations; ADME studies

Special Issue Information

Dear Colleagues,

This Special Issue is entitled “Medicinal Chemistry in Europe”. In Europe, many research groups, both from industry and academia, are working on medicinal chemistry topics that cover almost all therapeutic fields, ranging from anticancer and antimicrobial agents to compounds potentially active in severe cerebral pathologies, including Parkinson’s and Alzheimer’s diseases. Molecules devoted to the treatment of rare disease are also being investigated. The results obtained, frequently very important and recognized all over the world, are derived from the close collaboration of experts in different areas, such as computational chemistry, organic chemistry, biology, biochemistry and pharmacology.

Scientists from Europe are cordially invited to contribute original research papers or reviews to this Special Issue of Molecules, which reports on the design, synthesis, and evaluation of potentially-active compounds in the different subjects of medicinal chemistry.

Prof. Dr. Silvia Schenone
Guest Editor

* Silvia Schenone is a full professor of medicinal chemistry at the Pharmacy Department of the University of Genoa, Italy. She is involved in the design, synthesis and identification of organic molecules endowed with pharmacological activity. She is also interested in structural studies of biological macromolecules and molecular modeling applications in medicinal subjects. She started her work in the field of anti-inflammatory agents, then moved to adenosine receptor antagonists, and in the last few years she has been working on the design and synthesis of protein kinase inhibitors as anticancer agents. Her research on this last topic has led to the publication of 85 articles and four patents. Her other expertise is related to ADME (adsorption, distribution, metabolism and excretion) studies in silico, in vitro and in vivo. In many cases, to improve the bioavailability of the most active compounds, she has prepared and optimized different pharmaceutical formulations, including albumin nanoparticles, liposomes and cyclodextrine complexes. Recently, she has been involved in the synthesis of prodrugs which are particularly useful to improve the bioavailability of active compounds with poor water solubility, as in the case of the majority of protein kinase inhibitors. She collaborates with many groups of biologists and pharmacologists in Italy, Europe and USA. She is the author of 162 articles and of 6 patents.

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. Molecules 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 1800 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 discovery
  • biologically active compounds
  • anticancer agents
  • antimicrobial agents
  • analgesic and anti-inflammatory agents
  • CNS pathologies
  • rare diseases
  • cardiovascular diseases

Published Papers (10 papers)

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Research

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Open AccessFeature PaperArticle Exploring Alternative Radiolabeling Strategies for Sialic Acid-Binding Immunoglobulin-Like Lectin 9 Peptide: [68Ga]Ga- and [18F]AlF-NOTA-Siglec-9
Molecules 2018, 23(2), 305; https://doi.org/10.3390/molecules23020305
Received: 10 January 2018 / Revised: 26 January 2018 / Accepted: 29 January 2018 / Published: 31 January 2018
PDF Full-text (2833 KB) | HTML Full-text | XML Full-text
Abstract
Amino acid residues 283–297 from sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) form a cyclic peptide ligand targeting vascular adhesion protein-1 (VAP-1). VAP-1 is associated with the transfer of leukocytes from blood to tissues upon inflammation. Therefore, analogs of Siglec-9 peptide are good candidates
[...] Read more.
Amino acid residues 283–297 from sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) form a cyclic peptide ligand targeting vascular adhesion protein-1 (VAP-1). VAP-1 is associated with the transfer of leukocytes from blood to tissues upon inflammation. Therefore, analogs of Siglec-9 peptide are good candidates for visualizing inflammation non-invasively using positron emission tomography (PET). Gallium-68-labeled 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA)-conjugated Siglec-9 has been evaluated extensively for this purpose. Here, we explored two alternative strategies for radiolabeling Siglec-9 peptide using a 1,4,7-triazacyclononane-triacetic acid (NOTA)-chelator to bind [68Ga]Ga or [18F]AlF. The radioligands were evaluated by in vivo PET imaging and ex vivo γ-counting of turpentine-induced sterile skin/muscle inflammation in Sprague-Dawley rats. Both tracers showed clear accumulation in the inflamed tissues. The whole-body biodistribution patterns of the tracers were similar. Full article
(This article belongs to the Special Issue Medicinal Chemistry in Europe)
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Open AccessArticle Potent and Selective Carboxylic Acid Inhibitors of Tumor-Associated Carbonic Anhydrases IX and XII
Received: 29 November 2017 / Revised: 19 December 2017 / Accepted: 20 December 2017 / Published: 22 December 2017
Cited by 1 | PDF Full-text (3654 KB) | HTML Full-text | XML Full-text
Abstract
Selective inhibition of tumor-associated carbonic anhydrase (CA; EC 4.2.1.1) isoforms IX and XII is a crucial prerequisite to develop successful anticancer therapeutics. Herein, we confirmed the efficacy of the 3-nitrobenzoic acid substructure in the design of potent and selective carboxylic acid derivatives as
[...] Read more.
Selective inhibition of tumor-associated carbonic anhydrase (CA; EC 4.2.1.1) isoforms IX and XII is a crucial prerequisite to develop successful anticancer therapeutics. Herein, we confirmed the efficacy of the 3-nitrobenzoic acid substructure in the design of potent and selective carboxylic acid derivatives as CAs inhibitors. Compound 10 emerged as the most potent inhibitor of the tumor-associated hCA IX and XII (Ki = 16 and 82.1 nM, respectively) with a significant selectivity with respect to the wide spread hCA II. Other 3-nitrobenzoic acid derivatives showed a peculiar CA inhibition profile with a notable potency towards hCA IX. Full article
(This article belongs to the Special Issue Medicinal Chemistry in Europe)
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Open AccessArticle Rational Design of Nucleoside–Bile Acid Conjugates Incorporating a Triazole Moiety for Anticancer Evaluation and SAR Exploration
Molecules 2017, 22(10), 1710; https://doi.org/10.3390/molecules22101710
Received: 27 September 2017 / Revised: 9 October 2017 / Accepted: 10 October 2017 / Published: 12 October 2017
Cited by 1 | PDF Full-text (3500 KB) | HTML Full-text | XML Full-text
Abstract
Herein we report a study on the synthesis and biological evaluation of a library of nucleoside-bile acid conjugates prepared by combining 2′-deoxyadenosine, 2′-deoxyguanosine, 2′-deoxyuridine as well as adenosine and guanosine derivatives with cheno-, urso-, nor-cheno-, nor-urso- and taurourso-desoxycholic acid derivatives by
[...] Read more.
Herein we report a study on the synthesis and biological evaluation of a library of nucleoside-bile acid conjugates prepared by combining 2′-deoxyadenosine, 2′-deoxyguanosine, 2′-deoxyuridine as well as adenosine and guanosine derivatives with cheno-, urso-, nor-cheno-, nor-urso- and taurourso-desoxycholic acid derivatives by means of the click reaction. The new nucleoside-bile acid conjugates incorporating a triazole moiety were tested in vitro against leukemic K562 and HCT116 colon carcinoma, as well as on normal fibroblast cells. Six compounds displayed interesting anti-proliferative activity against the selected cancer lines and no cytotoxic effects against normal fibroblasts. A possible structure activity relationship was also investigated. Full article
(This article belongs to the Special Issue Medicinal Chemistry in Europe)
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Open AccessArticle Antifungal Activity of Thapsia villosa Essential Oil against Candida, Cryptococcus, Malassezia, Aspergillus and Dermatophyte Species
Molecules 2017, 22(10), 1595; https://doi.org/10.3390/molecules22101595
Received: 31 July 2017 / Revised: 18 September 2017 / Accepted: 20 September 2017 / Published: 22 September 2017
Cited by 1 | PDF Full-text (446 KB) | HTML Full-text | XML Full-text
Abstract
The composition of the essential oil (EO) of Thapsia villosa (Apiaceae), isolated by hydrodistillation from the plant’s aerial parts, was analysed by GC and GC-MS. Antifungal activity of the EO and its main components, limonene (57.5%) and methyleugenol (35.9%), were evaluated against clinically
[...] Read more.
The composition of the essential oil (EO) of Thapsia villosa (Apiaceae), isolated by hydrodistillation from the plant’s aerial parts, was analysed by GC and GC-MS. Antifungal activity of the EO and its main components, limonene (57.5%) and methyleugenol (35.9%), were evaluated against clinically relevant yeasts (Candida spp., Cryptococcus neoformans and Malassezia furfur) and moulds (Aspergillus spp. and dermatophytes). Minimum inhibitory concentrations (MICs) were measured according to the broth macrodilution protocols by Clinical and Laboratory Standards Institute (CLSI). The EO, limonene and methyleugenol displayed low MIC and MFC (minimum fungicidal concentration) values against Candida spp., Cryptococcus neoformans, dermatophytes, and Aspergillus spp. Regarding Candida species, an inhibition of yeast–mycelium transition was demonstrated at sub-inhibitory concentrations of the EO (MIC/128; 0.01 μL/mL) and their major compounds in Candida albicans. Fluconazole does not show this activity, and the combination with low concentrations of EO could associate a supplementary target for the antifungal activity. The association of fluconazole with T. villosa oil does not show antagonism, but the combination limonene/fluconazole displays synergism. The fungistatic and fungicidal activities revealed by T. villosa EO and its main compounds, associated with their low haemolytic activity, confirm their potential antimicrobial interest against fungal species often associated with human mycoses. Full article
(This article belongs to the Special Issue Medicinal Chemistry in Europe)
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Open AccessArticle Sulfadiazine Salicylaldehyde-Based Schiff Bases: Synthesis, Antimicrobial Activity and Cytotoxicity
Molecules 2017, 22(9), 1573; https://doi.org/10.3390/molecules22091573
Received: 25 August 2017 / Revised: 12 September 2017 / Accepted: 13 September 2017 / Published: 19 September 2017
Cited by 3 | PDF Full-text (1033 KB) | HTML Full-text | XML Full-text
Abstract
The resistance among microbes has brought an urgent need for new drugs. Thus, we synthesized a series of Schiff bases derived from the sulfa drug sulfadiazine and various salicylaldehydes. The resulting 4-[(2-hydroxybenzylidene)amino]-N-(pyrimidin-2-yl)benzene-sulfonamides were characterized and evaluated against Gram-positive and Gram-negative bacteria,
[...] Read more.
The resistance among microbes has brought an urgent need for new drugs. Thus, we synthesized a series of Schiff bases derived from the sulfa drug sulfadiazine and various salicylaldehydes. The resulting 4-[(2-hydroxybenzylidene)amino]-N-(pyrimidin-2-yl)benzene-sulfonamides were characterized and evaluated against Gram-positive and Gram-negative bacteria, yeasts, moulds, Mycobacterium tuberculosis, nontuberculous mycobacteria (M. kansasii, M. avium) and their cytotoxicity was determined. Among bacteria, the genus Staphylococcus, including methicillin-resistant S. aureus, showed the highest susceptibility, with minimum inhibitory concentration values from 7.81 µM. The growth of Candida sp. and Trichophyton interdigitale was inhibited at concentrations starting from 1.95 µM. 4-[(2,5-Dihydroxybenzylidene)amino]-N-(pyrimidin-2-yl)-benzenesulfonamide was identified as the most selective Schiff base for these strains with no apparent cytotoxicity and a selectivity index higher than 16. With respect to M. tuberculosis and M. kansasii that were inhibited within the range of 8 to 250 µM, unsubstituted 4-[(2-hydroxy-benzylidene)amino]-N-(pyrimidin-2-yl)benzenesulfonamide meets the selectivity requirement. In general, dihalogenation of the salicylic moiety improved the antibacterial and antifungal activity but also increased the cytotoxicity, especially with an increasing atomic mass. Some derivatives offer more advantageous properties than the parent sulfadiazine, thus constituting promising hits for further antimicrobial drug development. Full article
(This article belongs to the Special Issue Medicinal Chemistry in Europe)
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Open AccessArticle Chemoinformatic Database Building and in Silico Hit-Identification of Potential Multi-Targeting Bioactive Compounds Extracted from Mushroom Species
Molecules 2017, 22(9), 1571; https://doi.org/10.3390/molecules22091571
Received: 4 August 2017 / Revised: 13 September 2017 / Accepted: 17 September 2017 / Published: 19 September 2017
PDF Full-text (37028 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Mushrooms are widely-consumed fungi which contain natural compounds that can be used both for their nutritive and medicinal properties, i.e., taking advantage of their antimicrobial, antiviral, antitumor, anti-allergic, immunomodulation, anti-inflammatory, anti-atherogenic, hypoglycemic, hepatoprotective and antioxidant effects. Currently, scientific interest in natural compounds extracted
[...] Read more.
Mushrooms are widely-consumed fungi which contain natural compounds that can be used both for their nutritive and medicinal properties, i.e., taking advantage of their antimicrobial, antiviral, antitumor, anti-allergic, immunomodulation, anti-inflammatory, anti-atherogenic, hypoglycemic, hepatoprotective and antioxidant effects. Currently, scientific interest in natural compounds extracted from the fungal species is increasing because these compounds are also known to have pharmacological/biological activity. Unfortunately, however, their mechanisms of action are often unknown, not well understood or have not been investigated in their entirety. Given the poly-pharmacological properties of bioactive fungal compounds, it was decided to carry out a multi-targeted approach to predict possible interactions occurring among bioactive natural fungal extracts and several macromolecular targets that are therapeutically interesting, i.e., proteins, enzymes and nucleic acids. A chemical database of compounds extracted from both edible and no-edible mushrooms was created. This database was virtually screened against 43 macromolecular targets downloaded from the Protein Data Bank website. The aim of this work is to provide a molecular description of the main interactions involving ligand/multi-target recognition in order to understand the polypharmacological profile of the most interesting fungal extracts and to suggest a design strategy of new multi-target agents. Full article
(This article belongs to the Special Issue Medicinal Chemistry in Europe)
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Open AccessArticle Synthesis and Physicochemical Characterization of the Process-Related Impurities of Eplerenone, an Antihypertensive Drug
Molecules 2017, 22(8), 1354; https://doi.org/10.3390/molecules22081354
Received: 28 July 2017 / Accepted: 11 August 2017 / Published: 15 August 2017
Cited by 1 | PDF Full-text (6941 KB) | HTML Full-text | XML Full-text
Abstract
Two unknown impurities were observed during the process development for multigram-scale synthesis of eplerenone (Inspra®). The new process-related impurities were identified and fully characterized as the corresponding (7β,11α,17α)-11-hydroxy- and (7α,11β,17α)-9,11-dichloroeplerenone derivatives 12a and 13. Seven other known but poorly described
[...] Read more.
Two unknown impurities were observed during the process development for multigram-scale synthesis of eplerenone (Inspra®). The new process-related impurities were identified and fully characterized as the corresponding (7β,11α,17α)-11-hydroxy- and (7α,11β,17α)-9,11-dichloroeplerenone derivatives 12a and 13. Seven other known but poorly described in the literature eplerenone impurities, including four impurities A, B, C and E listed in the European Pharmacopoeia 8.4 were also detected, identified and fully characterized. All these contaminants result from side reactions taking place on the steroid ring C of the starting 11α-hydroxy-7α-(methoxycarbonyl)-3-oxo-17α-pregn-4-ene-21,17-carbolactone (12) and the key intermediate (7α,17α)-9(11)-enester 7, including epimerization of the C-7 asymmetric center, oxidation, dehydration, chlorination and lactonization. The impurities were isolated and/or synthesized and fully characterized by infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI). Their 1H- and 13C-NMR signals were fully assigned. The molecular structures of the eight impurities, including the new (7β,11α,17α)-11-hydroxy- and (7α,11β,17α)-9,11-dichloroeplerenone related substances 12a and 13, were solved and refined using single-crystal X-ray diffraction (SCXRD). The full identification and characterization of these impurities should be useful for the quality control and the validation of the analytical methods in the manufacture of eplerenone. Full article
(This article belongs to the Special Issue Medicinal Chemistry in Europe)
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Review

Jump to: Research

Open AccessReview Clinically Applicable Inhibitors Impacting Genome Stability
Molecules 2018, 23(5), 1166; https://doi.org/10.3390/molecules23051166
Received: 21 March 2018 / Revised: 27 April 2018 / Accepted: 1 May 2018 / Published: 13 May 2018
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Abstract
Advances in technology have facilitated the molecular profiling (genomic and transcriptomic) of tumours, and has led to improved stratification of patients and the individualisation of treatment regimes. To fully realize the potential of truly personalised treatment options, we need targeted therapies that precisely
[...] Read more.
Advances in technology have facilitated the molecular profiling (genomic and transcriptomic) of tumours, and has led to improved stratification of patients and the individualisation of treatment regimes. To fully realize the potential of truly personalised treatment options, we need targeted therapies that precisely disrupt the compensatory pathways identified by profiling which allow tumours to survive or gain resistance to treatments. Here, we discuss recent advances in novel therapies that impact the genome (chromosomes and chromatin), pathways targeted and the stage of the pathways targeted. The current state of research will be discussed, with a focus on compounds that have advanced into trials (clinical and pre-clinical). We will discuss inhibitors of specific DNA damage responses and other genome stability pathways, including those in development, which are likely to synergistically combine with current therapeutic options. Tumour profiling data, combined with the knowledge of new treatments that affect the regulation of essential tumour signalling pathways, is revealing fundamental insights into cancer progression and resistance mechanisms. This is the forefront of the next evolution of advanced oncology medicine that will ultimately lead to improved survival and may, one day, result in many cancers becoming chronic conditions, rather than fatal diseases. Full article
(This article belongs to the Special Issue Medicinal Chemistry in Europe)
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Open AccessReview Transdermal and Topical Drug Administration in the Treatment of Pain
Molecules 2018, 23(3), 681; https://doi.org/10.3390/molecules23030681
Received: 30 January 2018 / Revised: 12 March 2018 / Accepted: 13 March 2018 / Published: 17 March 2018
Cited by 1 | PDF Full-text (777 KB) | HTML Full-text | XML Full-text
Abstract
The comprehensive treatment of pain is multidimodal, with pharmacotherapy playing a key role. An effective therapy for pain depends on the intensity and type of pain, the patients’ age, comorbidities, and appropriate choice of analgesic, its dose and route of administration. This review
[...] Read more.
The comprehensive treatment of pain is multidimodal, with pharmacotherapy playing a key role. An effective therapy for pain depends on the intensity and type of pain, the patients’ age, comorbidities, and appropriate choice of analgesic, its dose and route of administration. This review is aimed at presenting current knowledge on analgesics administered by transdermal and topical routes for physicians, nurses, pharmacists, and other health care professionals dealing with patients suffering from pain. Analgesics administered transdermally or topically act through different mechanisms. Opioids administered transdermally are absorbed into vessels located in subcutaneous tissue and, subsequently, are conveyed in the blood to opioid receptors localized in the central and peripheral nervous system. Non–steroidal anti–inflammatory drugs (NSAIDs) applied topically render analgesia mainly through a high concentration in the structures of the joint and a provision of local anti–inflammatory effects. Topically administered drugs such as lidocaine and capsaicin in patches, capsaicin in cream, EMLA cream, and creams containing antidepressants (i.e., doxepin, amitriptyline) act mainly locally in tissues through receptors and/or ion channels. Transdermal and topical routes offer some advantages over systemic analgesic administration. Analgesics administered topically have a much better profile for adverse effects as they relieve local pain with minimal systemic effects. The transdermal route apart from the above-mentioned advantages and provision of long period of analgesia may be more convenient, especially for patients who are unable to take drugs orally. Topically and transdermally administered opioids are characterised by a lower risk of addiction compared to oral and parenteral routes. Full article
(This article belongs to the Special Issue Medicinal Chemistry in Europe)
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Open AccessFeature PaperReview Three-Dimensional Analysis of the Interactions between hLDH5 and Its Inhibitors
Molecules 2017, 22(12), 2217; https://doi.org/10.3390/molecules22122217
Received: 17 November 2017 / Revised: 10 December 2017 / Accepted: 12 December 2017 / Published: 13 December 2017
PDF Full-text (3012 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Inhibitors of human lactate dehydrogenase (hLDH5)—the enzyme responsible for the conversion of pyruvate to lactate coupled with oxidation of NADH to NAD+—are promising therapeutic agents against cancer because this enzyme is generally found to be overexpressed in most invasive
[...] Read more.
Inhibitors of human lactate dehydrogenase (hLDH5)—the enzyme responsible for the conversion of pyruvate to lactate coupled with oxidation of NADH to NAD+—are promising therapeutic agents against cancer because this enzyme is generally found to be overexpressed in most invasive cancer cells and is linked to their vitality especially under hypoxic conditions. Consequently, significant efforts have been made for the identification of small-molecule hLDH5 inhibitors displaying high inhibitory potencies. X-ray structure of hLDH5 complexes as well as molecular modeling studies contribute to identify and explain the main binding modes of hLDH5 inhibitors reported in literature. The purpose of this review is to analyze the main three-dimensional interactions between some of the most potent inhibitors and hLDH5, in order to provide useful suggestions for the design of new derivatives. Full article
(This article belongs to the Special Issue Medicinal Chemistry in Europe)
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