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Exclusive Papers from the Editorial Board Members (EBMs) of the Section “Medicinal Chemistry” of Molecules

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

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 10929

Special Issue Editors

Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Avenue Joan XXIII, 27-31, E-08028 Barcelona, Spain
Interests: multitarget anti-Alzheimer agents; hybrid compounds; cholinesterase inhibitors; amyloid anti-aggregating compounds; BACE-1 inhibitors; antiprotozoan compounds
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Institute of Pharmacy, Department of Pharmaceutical Chemistry, Center for Molecular Biosciences (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Interests: opioid receptors; opioid pharmacology; pain research; CNS disorders; opioid drug discovery; structure-activity-relationships; GPCRs signalling
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Department of Pharmacy and Biotechnology, Alma Mater Studiorum—University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy
Interests: medicinal chemistry; natural products; curcumin; drug design; multitarget drug discovery; bioactive compounds; neurodegeneration; cancer
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Department of Food Science and Technology, University of West Attica, Athens, Greece
Interests: molecular design; bioanalysis; natural bioactive compounds; computational chemistry; analytical chemistry
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
Interests: innovative drug research; antiviral drug; drug design; medicinal chemistry; antigout drug
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Special Issue Information

Dear Colleagues,

This Special Issue of Molecules is dedicated to recent advances in medicinal chemistry research areas and comprises a diverse selection of exclusive papers from the Editorial Board Members (EBMs) of the Section Medicinal Chemistry. It focuses on highlighting recent interesting investigations conducted in the laboratories of our section’s EBMs and aims to represent our section as an attractive open-access publishing platform for medicinal chemistry research.

Dr. Diego Muñoz-Torrero
Prof. Dr. Mariana Spetea
Dr. Federica Belluti
Dr. Panagiotis Zoumpoulakis
Prof. Dr. Xinyong Liu
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.

Published Papers (6 papers)

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Research

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12 pages, 3174 KiB  
Article
Suramin Disturbs the Association of the N-Terminal Domain of SARS-CoV-2 Nucleocapsid Protein with RNA
by Chenyun Guo, Hao Xu, Xiao Li, Jiaxin Yu and Donghai Lin
Molecules 2023, 28(6), 2534; https://doi.org/10.3390/molecules28062534 - 10 Mar 2023
Cited by 1 | Viewed by 1189
Abstract
Suramin was originally used as an antiparasitic drug in clinics. Here, we demonstrate that suramin can bind to the N-terminal domain of SARS-CoV-2 nucleocapsid protein (N-NTD) and disturb its interaction with RNA. The BLI experiments showed that N-NTD interacts suramin with a dissociate [...] Read more.
Suramin was originally used as an antiparasitic drug in clinics. Here, we demonstrate that suramin can bind to the N-terminal domain of SARS-CoV-2 nucleocapsid protein (N-NTD) and disturb its interaction with RNA. The BLI experiments showed that N-NTD interacts suramin with a dissociate constant (Kd = 2.74 μM) stronger than that of N-NTD with ssRNA-16 (Kd = 8.37 μM). Furthermore, both NMR titration experiments and molecular docking analysis suggested that suramin mainly binds to the positively charged cavity between the finger and the palm subdomains of N-NTD, and residues R88, R92, R93, I94, R95, K102 and A156 are crucial for N-NTD capturing suramin. Besides, NMR dynamics experiments showed that suramin-bound N-NTD adopts a more rigid structure, and the loop between β2-β3 exhibits fast motion on the ps-ns timescale, potentially facilitating suramin binding. Our findings not only reveal the molecular basis of suramin disturbing the association of SARS-CoV-2 N-NTD with RNA but also provide valuable structural information for the development of drugs against SARS-CoV-2. Full article
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34 pages, 7884 KiB  
Article
Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAFV600E Protein
by Elisabetta Marini, Marco Marino, Giulia Gionfriddo, Federica Maione, Marta Pandini, Daniele Oddo, Marta Giorgis, Barbara Rolando, Federica Blua, Simone Gastaldi, Serena Marchiò, Sandra Kovachka, Francesca Spyrakis, Eleonora Gianquinto, Federica Di Nicolantonio and Massimo Bertinaria
Molecules 2022, 27(23), 8513; https://doi.org/10.3390/molecules27238513 - 03 Dec 2022
Cited by 5 | Viewed by 2479
Abstract
BRAF is a serine/threonine kinase frequently mutated in human cancers. BRAFV600E mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, their long-term efficacy is hampered by resistance mechanisms. The PROTAC-induced degradation of [...] Read more.
BRAF is a serine/threonine kinase frequently mutated in human cancers. BRAFV600E mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, their long-term efficacy is hampered by resistance mechanisms. The PROTAC-induced degradation of BRAFV600E has been proposed as an alternative strategy to avoid the onset of resistance. In this study, we designed a series of compounds where the BRAF kinase inhibitor encorafenib was conjugated to pomalidomide through different linkers. The synthesized compounds maintained their ability to inhibit the kinase activity of mutated BRAF with IC50 values in the 40–88 nM range. Selected compounds inhibited BRAFV600E signaling and cellular proliferation of A375 and Colo205 tumor cell lines. Compounds 10 and 11, the most active of the series, were not able to induce degradation of mutated BRAF. Docking and molecular dynamic studies, conducted in comparison with the efficient BRAF degrader P5B, suggest that a different orientation of the linker bearing the pomalidomide substructure, together with a decreased mobility of the solvent-exposed part of the conjugates, could explain this behavior. Full article
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14 pages, 2437 KiB  
Article
Sirtuin 1-Activating Compounds: Discovery of a Class of Thiazole-Based Derivatives
by Giulia Bononi, Valentina Citi, Margherita Lapillo, Alma Martelli, Giulio Poli, Tiziano Tuccinardi, Carlotta Granchi, Lara Testai, Vincenzo Calderone and Filippo Minutolo
Molecules 2022, 27(19), 6535; https://doi.org/10.3390/molecules27196535 - 03 Oct 2022
Cited by 6 | Viewed by 2273
Abstract
Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase implicated in various biological and pathological processes, including cancer, diabetes, and cardiovascular diseases. In recent years, SIRT1-activating compounds have been demonstrated to exert cardioprotective effects. Therefore, this enzyme has become a feasible target to [...] Read more.
Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase implicated in various biological and pathological processes, including cancer, diabetes, and cardiovascular diseases. In recent years, SIRT1-activating compounds have been demonstrated to exert cardioprotective effects. Therefore, this enzyme has become a feasible target to treat cardiovascular diseases, and many SIRT1 activators, of a natural or synthetic origin, have been identified. In the present work, we developed thiazole-based SIRT1 activators, which showed remarkably higher SIRT1 activation potencies compared with those of the reference compound resveratrol when tested in enzymatic assays. Thiazole 8, a representative compound of this series, was also subjected to further pharmacological investigations, where it was proven to reduce myocardial damage induced by an in vivo occlusion/reperfusion event, thus confirming its cardioprotective properties. In addition, the cardioprotective effect of compound 8 was significantly higher than that of resveratrol. Molecular modeling studies suggest the binding mode of these derivatives within SIRT1 in the presence of the p53-AMC peptide. These promising results could pave the way to further expand and optimize this chemical class of new and potent SIRT1 activators as potential cardioprotective agents. Full article
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10 pages, 1608 KiB  
Communication
Investigation on the Peroxidase-like Activity of Vitamin B6 and Its Applications in Colorimetric Detection of Hydrogen Peroxide and Total Antioxidant Capacity Evaluation
by Chun-Yan Zhang, Li-Jing Peng, Guo-Ying Chen, Hao Zhang and Feng-Qing Yang
Molecules 2022, 27(13), 4262; https://doi.org/10.3390/molecules27134262 - 01 Jul 2022
Cited by 1 | Viewed by 1704
Abstract
The peroxidase-like activity of vitamin B6 (VB6) was firstly demonstrated by catalyzing the peroxidase chromogenic substrate 3,3′,5,5′-tetramethylbenzidine (TMB) at the existence of H2O2. The influence of different factors on the catalytic property of VB6, including pH, temperature, VB6 concentration, [...] Read more.
The peroxidase-like activity of vitamin B6 (VB6) was firstly demonstrated by catalyzing the peroxidase chromogenic substrate 3,3′,5,5′-tetramethylbenzidine (TMB) at the existence of H2O2. The influence of different factors on the catalytic property of VB6, including pH, temperature, VB6 concentration, and incubation time, were investigated. The steady-state kinetic study results indicate that VB6 possesses higher affinity to H2O2 than natural horseradish peroxidase and some other peroxidase mimics. Besides, the radical quenching experiment results confirm that hydroxyl radical (•OH) accounts for the catalytic process. Based on the excellent peroxidase-like catalytic activity of VB6, the colorimetric methods for H2O2 and gallic acid (GA) detection were developed by measuring the absorbance variance of the catalytic system. Under the optimal conditions, the linear ranges of the methods for H2O2 and GA determination with good selectivity are 50.0–600.0 μM and 10.0–50.0 μM, respectively. In addition, the developed method was applied in the detection of H2O2 in milk samples and evaluation of total antioxidant capacity of different tea infusions. This study may broaden the application prospect of VB6 in environmental and biomedical analysis fields, contribute to profound insight of the physiological functions of VB6, as well as lay foundation for further excavation of small-molecule peroxidase mimics. Full article
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Review

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26 pages, 2847 KiB  
Review
Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain
by Helmut Schmidhammer, Mahmoud Al-Khrasani, Susanna Fürst and Mariana Spetea
Molecules 2023, 28(12), 4761; https://doi.org/10.3390/molecules28124761 - 14 Jun 2023
Cited by 2 | Viewed by 1045
Abstract
Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of currently available opioids, together with the current ‘opioid crisis’, warrant consideration on new opioid analgesic discovery strategies. Targeting peripheral [...] Read more.
Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of currently available opioids, together with the current ‘opioid crisis’, warrant consideration on new opioid analgesic discovery strategies. Targeting peripheral opioid receptors as effective means of treating pain and avoiding the centrally mediated side effects represents a research area of substantial and continuous attention. Among clinically used analgesics, opioids from the class of morphinans (i.e., morphine and structurally related analogues) are of utmost clinical importance as analgesic drugs activating the mu-opioid receptor. In this review, we focus on peripheralization strategies applied to N-methylmorphinans to limit their ability to cross the blood–brain barrier, thus minimizing central exposure and the associated undesired side effects. Chemical modifications to the morphinan scaffold to increase hydrophilicity of known and new opioids, and nanocarrier-based approaches to selectively deliver opioids, such as morphine, to the peripheral tissue are discussed. The preclinical and clinical research activities have allowed for the characterization of a variety of compounds that show low central nervous system penetration, and therefore an improved side effect profile, yet maintaining the desired opioid-related antinociceptive activity. Such peripheral opioid analgesics may represent alternatives to presently available drugs for an efficient and safer pain therapy. Full article
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Other

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9 pages, 1239 KiB  
Brief Report
Repurposing the Antiplatelet Agent Ticlopidine to Counteract the Acute Phase of ER Stress Condition: An Opportunity for Fighting Coronavirus Infections and Cancer
by Anna Tesei, Michela Cortesi, Martina Bedeschi, Noemi Marino, Giacomo Rossino, Roberta Listro, Daniela Rossi, Pasquale Linciano and Simona Collina
Molecules 2022, 27(14), 4327; https://doi.org/10.3390/molecules27144327 - 06 Jul 2022
Cited by 1 | Viewed by 1504
Abstract
Different pathological conditions, including viral infections and cancer, can have a massive impact on the endoplasmic reticulum (ER), causing severe damage to the cell and exacerbating the disease. In particular, coronavirus infections, including SARS coronavirus-2 (SARS-CoV-2), responsible for COVID-19, cause ER stress as [...] Read more.
Different pathological conditions, including viral infections and cancer, can have a massive impact on the endoplasmic reticulum (ER), causing severe damage to the cell and exacerbating the disease. In particular, coronavirus infections, including SARS coronavirus-2 (SARS-CoV-2), responsible for COVID-19, cause ER stress as a consequence of the enormous amounts of viral glycoproteins synthesized, the perturbation of ER homeostasis and the modification of ER membranes. Therefore, ER has a central role in the viral life cycle, thus representing one of the Achilles’ heels on which to focus therapeutic intervention. On the other hand, prolonged ER stress has been demonstrated to promote many pro-tumoral attributes in cancer cells, having a key role in tumor growth, metastasis and response to therapies. In this report, adopting a repurposing approach of approved drugs, we identified the antiplatelet agent ticlopidine as an interferent of the unfolded protein response (UPR) via sigma receptors (SRs) modulation. The promising results obtained suggest the potential use of ticlopidine to counteract ER stress induced by viral infections, such as COVID-19, and cancer. Full article
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