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Special Issue "Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes 2020"

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

Deadline for manuscript submissions: closed (31 December 2020).

Special Issue Editor

Prof. Dr. Diego Muñoz-Torrero
E-Mail Website1 Website2
Guest Editor
Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Av. 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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In May 2017 the Medicinal Chemistry section of Molecules launched the series of Editorials Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes [1], which are published on a biannual basis. In these Editorials, the section Editorial Board highlight in brief reports (of about one hundred words) selected recent articles from all publishers that describe groundbreaking findings, such as the discovery of novel drug targets and mechanisms of action or novel classes of drugs, which are expected to inspire future Medicinal Chemistry endeavors devoted to addressing prime unmet medical needs. Encouraged by the good acceptance of this series of Editorials, and in a further effort to improve our services for the Medicinal Chemistry community, we have decided to go beyond the brief highlights of the Editorials by setting up a parallel Topical Collection, with the same name. The Topical Collection will consist of a series of special issues to be published annually, which will collect provoking Comments, Opinions, Perspectives, Reviews and Original Research Articles that focus on the hot topics that have been highlighted in the two previously published Editorials. These regular longer-form contributions will elaborate on the background of the hot topics selected in the Editorials, to better outlining the high potential of these works and shaping future Medicinal Chemistry and Drug Discovery strategies. Thus, this Topical Collection will be a unique platform to be aware in a timely manner of the current greatest challenges and most promising discoveries in the Medicinal Chemistry and Drug Discovery field.

  1. Muñoz-Torrero, D.; Mangoni, A. A.; Guillou, C.; Collina, S.; Vanden Eynde, J. J.; Rautio, J.; Keseru, G. M.; Hulme, C.; Chibale, K.; Luque, F. J.; Karaman, R.; Gütschow, M.; Liu, H.; Ragno, R. Breakthroughs in Medicinal Chemistry: New targets and mechanisms, new drugs, new hopes. Molecules 2017, 22, 743.

Hot Topics in 2020

Special Issue Open for Submission

Special Issue Pending Online

  • Alzheimer's Disease Causes and Approaches for Treatment
  • Anticancer Drug Design
  • Development of a Target Fishing In Silico Platform
  • Development of New Antimicrobial Agents against Resistant Strains
  • Discovering New Drugs against Tropical/Neglected Diseases
  • DNA-based Multivalent Molecules
  • Exploring the Ligandability of Human Proteome with Functionalized Enantiomeric Probes
  • Further Development of Antibody Drugs
  • Future Developments in Self-Assembled Antimicrobial Peptides
  • Inflammasome, A Promising Therapeutic Biological Target
  • Inventive Approaches for Cancer Targeted Therapy
  • Metalloenzyme Inhibitors as Anticancer Agents
  • Nature Inspired Design of Small Molecular Weight Compounds: Practicable Synthetic Routes to New Anticancer Drugs
  • New Approaches in Antitumoral Therapy
  • New Apportunities for Antimicrobial Peptides as Anticancer Agents
  • New Pan-β-Lactamases Inhibitors
  • New Trends in Siderophores Chemistry
  • Novel Prodrug Strategies
  • Novel Strategies against Resistant Pathogens
  • Novel Therapeutic Agents Targeting Multiple Pathways in Dementia and Neurodegeneration
  • Photoactivatable Molecules
  • Proteolysis Targeting Chimera (PROTAC)
  • Synthesis and Evaluation of Radiopharmaceuticals
  • Targeting Cancer Stem Cells
  • Targeting Innate Immunity for Antiviral Therapy
  • Tauopathies
  • The Endocannabinoid System: Novel Targets for Treating Neurological Disorders
  • The Quest for Increasingly Accurate In Silico Tools to Predict Druggability
  • The Search for New Drugs against Gram-Negative Bacteria

Prof. Dr. Diego Muñoz-Torrero
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. 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 2000 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.

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Published Papers (10 papers)

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Editorial

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Editorial
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–7
Molecules 2020, 25(13), 2968; https://doi.org/10.3390/molecules25132968 - 28 Jun 2020
Cited by 2 | Viewed by 3334
Abstract
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of editorials which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...] Full article
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Editorial
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6
Molecules 2020, 25(1), 119; https://doi.org/10.3390/molecules25010119 - 28 Dec 2019
Cited by 3 | Viewed by 4025
Abstract
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...] Full article
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Research

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Article
Permeation of β-Lactamase Inhibitors through the General Porins of Gram-Negative Bacteria
Molecules 2020, 25(23), 5747; https://doi.org/10.3390/molecules25235747 - 05 Dec 2020
Cited by 2 | Viewed by 724
Abstract
Modern medicine relies upon antibiotics, but we have arrived to the point where our inability to come up with new effective molecules against resistant pathogens, together with the declining private investment, is resulting in the number of untreatable infections increasing worldwide at worrying [...] Read more.
Modern medicine relies upon antibiotics, but we have arrived to the point where our inability to come up with new effective molecules against resistant pathogens, together with the declining private investment, is resulting in the number of untreatable infections increasing worldwide at worrying pace. Among other pathogens, widely recognized institutions have indicated Gram-negative bacteria as particularly challenging, due to the presence of the outer membrane. The very first step in the action of every antibiotic or adjuvant is the permeation through this membrane, with small hydrophilic drugs usually crossing through protein channels. Thus, a detailed understanding of their properties at a molecular level is crucial. By making use of Molecular Dynamics simulations, we compared the two main porins of four members of the Enterobacteriaceae family, and, in this paper, we show their shared geometrical and electrostatic characteristics. Then, we used metadynamics simulations to reconstruct the free energy for permeation of selected diazobicyclooctans through OmpF. We demonstrate how porins features are coupled to those of the translocating species, modulating their passive permeation. In particular, we show that the minimal projection area of a molecule is a better descriptor than its molecular mass or the volume. Together with the magnitude and orientation of the electric dipole moment, these are the crucial parameters to gain an efficient compensation between the entropic and enthalpic contributions to the free energy barrier required for permeation. Our results confirm the possibility to predict the permeability of molecules through porins by using a few molecular parameters and bolster the general model according to which the free energy increase is mostly due to the decrease of conformational entropy, and this can be compensated by a favorable alignment of the electric dipole with respect to the channel intrinsic electric field. Full article
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Article
Anion Inhibition Studies of the Beta-Carbonic Anhydrase from Escherichia coli
Molecules 2020, 25(11), 2564; https://doi.org/10.3390/molecules25112564 - 31 May 2020
Cited by 7 | Viewed by 1051
Abstract
The interconversion of CO2 and HCO3 is catalyzed by a superfamily of metalloenzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1), which maintain the equilibrium between dissolved inorganic CO2 and HCO3. In the genome of Escherichia coli [...] Read more.
The interconversion of CO2 and HCO3 is catalyzed by a superfamily of metalloenzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1), which maintain the equilibrium between dissolved inorganic CO2 and HCO3. In the genome of Escherichia coli, a Gram-negative bacterium typically colonizing the lower intestine of warm-blooded organisms, the cyn operon gene includes the CynT gene, encoding for a β-CA, and CynS gene, encoding for the cyanase. CynT (β-CA) prevents the depletion of the cellular bicarbonate, which is further used in the reaction catalyzed by cyanase. A second β-CA (CynT2 or Can or yadF), as well as a γ and ι-CAs were also identified in the E. coli genome. CynT2 is essential for bacterial growth at atmospheric CO2 concentration. Here, we characterized the kinetic properties and the anion inhibition profiles of recombinant CynT2. The enzyme showed a good activity for the physiological CO2 hydratase reaction with the following parameters: kcat = 5.3 × 105 s−1 and kcat/KM = of 4.1 × 107 M−1 s−1. Sulfamide, sulfamate, phenylboronic acid, phenylarsonic acid, and diethyldithiocarbamate were the most effective CynT2 inhibitors (KI = 2.5 to 84 µM). The anions allowed for a detailed understanding of the interaction of inhibitors with the amino acid residues surrounding the catalytic pocket of the enzyme and may be used as leads for the design of more efficient and specific inhibitors. Full article
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Review

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Review
Comprehensive Review on Alzheimer’s Disease: Causes and Treatment
Molecules 2020, 25(24), 5789; https://doi.org/10.3390/molecules25245789 - 08 Dec 2020
Cited by 51 | Viewed by 11815
Abstract
Alzheimer’s disease (AD) is a disorder that causes degeneration of the cells in the brain and it is the main cause of dementia, which is characterized by a decline in thinking and independence in personal daily activities. AD is considered a multifactorial disease: [...] Read more.
Alzheimer’s disease (AD) is a disorder that causes degeneration of the cells in the brain and it is the main cause of dementia, which is characterized by a decline in thinking and independence in personal daily activities. AD is considered a multifactorial disease: two main hypotheses were proposed as a cause for AD, cholinergic and amyloid hypotheses. Additionally, several risk factors such as increasing age, genetic factors, head injuries, vascular diseases, infections, and environmental factors play a role in the disease. Currently, there are only two classes of approved drugs to treat AD, including inhibitors to cholinesterase enzyme and antagonists to N-methyl d-aspartate (NMDA), which are effective only in treating the symptoms of AD, but do not cure or prevent the disease. Nowadays, the research is focusing on understanding AD pathology by targeting several mechanisms, such as abnormal tau protein metabolism, β-amyloid, inflammatory response, and cholinergic and free radical damage, aiming to develop successful treatments that are capable of stopping or modifying the course of AD. This review discusses currently available drugs and future theories for the development of new therapies for AD, such as disease-modifying therapeutics (DMT), chaperones, and natural compounds. Full article
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Review
Photoactivatable Platinum-Based Anticancer Drugs: Mode of Photoactivation and Mechanism of Action
Molecules 2020, 25(21), 5167; https://doi.org/10.3390/molecules25215167 - 06 Nov 2020
Cited by 6 | Viewed by 868
Abstract
Platinum-based anticancer drugs are a class of widely used agents in clinical cancer treatment. However, their efficacy was greatly limited by their severe side effects and the arising drug resistance. The selective activation of inert platinum-based drugs in the tumor site by light [...] Read more.
Platinum-based anticancer drugs are a class of widely used agents in clinical cancer treatment. However, their efficacy was greatly limited by their severe side effects and the arising drug resistance. The selective activation of inert platinum-based drugs in the tumor site by light irradiation is able to reduce side effects, and the novel mechanism of action of photoactivatable platinum drugs might also conquer the resistance. In this review, the recent advances in the design of photoactivatable platinum-based drugs were summarized. The complexes are classified according to their mode of action, including photoreduction, photo-uncaging, and photodissociation. The rationale of drug design, dark stability, photoactivation process, cytotoxicity, and mechanism of action of typical photoactivatable platinum drugs were reviewed. Finally, the challenges and opportunities for designing more potent photoactivatable platinum drugs were discussed. Full article
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Review
Lysosomotropic Features and Autophagy Modulators among Medical Drugs: Evaluation of Their Role in Pathologies
Molecules 2020, 25(21), 5052; https://doi.org/10.3390/molecules25215052 - 30 Oct 2020
Cited by 2 | Viewed by 819
Abstract
The concept of lysosomotropic agents significantly changed numerous aspects of cellular biochemistry, biochemical pharmacology, and clinical medicine. In the present review, we focused on numerous low-molecular and high-molecular lipophilic basic compounds and on the role of lipophagy and autophagy in experimental and clinical [...] Read more.
The concept of lysosomotropic agents significantly changed numerous aspects of cellular biochemistry, biochemical pharmacology, and clinical medicine. In the present review, we focused on numerous low-molecular and high-molecular lipophilic basic compounds and on the role of lipophagy and autophagy in experimental and clinical medicine. Attention was primarily focused on the most promising agents acting as autophagy inducers, which offer a new window for treatment and/or prophylaxis of various diseases, including type 2 diabetes mellitus, Parkinson’s disease, and atherosclerosis. The present review summarizes current knowledge on the lysosomotropic features of medical drugs, as well as autophagy inducers, and their role in pathological processes. Full article
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Review
Boronic Acids and Their Derivatives in Medicinal Chemistry: Synthesis and Biological Applications
Molecules 2020, 25(18), 4323; https://doi.org/10.3390/molecules25184323 - 21 Sep 2020
Cited by 12 | Viewed by 1899
Abstract
Boron containing compounds have not been widely studied in Medicinal Chemistry, mainly due to the idea that this group could confer some toxicity. Nowadays, this concept has been demystified and, especially after the discovery of the drug bortezomib, the interest for these compounds, [...] Read more.
Boron containing compounds have not been widely studied in Medicinal Chemistry, mainly due to the idea that this group could confer some toxicity. Nowadays, this concept has been demystified and, especially after the discovery of the drug bortezomib, the interest for these compounds, mainly boronic acids, has been growing. In this review, several activities of boronic acids, such as anticancer, antibacterial, antiviral activity, and even their application as sensors and delivery systems are addressed. The synthetic processes used to obtain these active compounds are also referred. Noteworthy, the molecular modification by the introduction of boronic acid group to bioactive molecules has shown to modify selectivity, physicochemical, and pharmacokinetic characteristics, with the improvement of the already existing activities. Besides, the preparation of compounds with this chemical group is relatively simple and well known. Taking into consideration these findings, this review reinforces the relevance of extending the studies with boronic acids in Medicinal Chemistry, in order to obtain new promising drugs shortly. Full article
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Review
Resistance of Gram-Positive Bacteria to Current Antibacterial Agents and Overcoming Approaches
Molecules 2020, 25(12), 2888; https://doi.org/10.3390/molecules25122888 - 23 Jun 2020
Cited by 21 | Viewed by 3075
Abstract
The discovery of antibiotics has created a turning point in medical interventions to pathogenic infections, but unfortunately, each discovery was consistently followed by the emergence of resistance. The rise of multidrug-resistant bacteria has generated a great challenge to treat infections caused by bacteria [...] Read more.
The discovery of antibiotics has created a turning point in medical interventions to pathogenic infections, but unfortunately, each discovery was consistently followed by the emergence of resistance. The rise of multidrug-resistant bacteria has generated a great challenge to treat infections caused by bacteria with the available antibiotics. Today, research is active in finding new treatments for multidrug-resistant pathogens. In a step to guide the efforts, the WHO has published a list of the most dangerous bacteria that are resistant to current treatments and requires the development of new antibiotics for combating the resistance. Among the list are various Gram-positive bacteria that are responsible for serious healthcare and community-associated infections. Methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and drug-resistant Streptococcus pneumoniae are of particular concern. The resistance of bacteria is an evolving phenomenon that arises from genetic mutations and/or acquired genomes. Thus, antimicrobial resistance demands continuous efforts to create strategies to combat this problem and optimize the use of antibiotics. This article aims to provide a review of the most critical resistant Gram-positive bacterial pathogens, their mechanisms of resistance, and the new treatments and approaches reported to circumvent this problem. Full article
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Review
Resistance of Gram-Negative Bacteria to Current Antibacterial Agents and Approaches to Resolve It
Molecules 2020, 25(6), 1340; https://doi.org/10.3390/molecules25061340 - 16 Mar 2020
Cited by 130 | Viewed by 7010
Abstract
Antimicrobial resistance represents an enormous global health crisis and one of the most serious threats humans face today. Some bacterial strains have acquired resistance to nearly all antibiotics. Therefore, new antibacterial agents are crucially needed to overcome resistant bacteria. In 2017, the World [...] Read more.
Antimicrobial resistance represents an enormous global health crisis and one of the most serious threats humans face today. Some bacterial strains have acquired resistance to nearly all antibiotics. Therefore, new antibacterial agents are crucially needed to overcome resistant bacteria. In 2017, the World Health Organization (WHO) has published a list of antibiotic-resistant priority pathogens, pathogens which present a great threat to humans and to which new antibiotics are urgently needed the list is categorized according to the urgency of need for new antibiotics as critical, high, and medium priority, in order to guide and promote research and development of new antibiotics. The majority of the WHO list is Gram-negative bacterial pathogens. Due to their distinctive structure, Gram-negative bacteria are more resistant than Gram-positive bacteria, and cause significant morbidity and mortality worldwide. Several strategies have been reported to fight and control resistant Gram-negative bacteria, like the development of antimicrobial auxiliary agents, structural modification of existing antibiotics, and research into and the study of chemical structures with new mechanisms of action and novel targets that resistant bacteria are sensitive to. Research efforts have been made to meet the urgent need for new treatments; some have succeeded to yield activity against resistant Gram-negative bacteria by deactivating the mechanism of resistance, like the action of the β-lactamase Inhibitor antibiotic adjuvants. Another promising trend was by referring to nature to develop naturally derived agents with antibacterial activity on novel targets, agents such as bacteriophages, DCAP(2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2(hydroxymethyl)propane1,3-diol, Odilorhabdins (ODLs), peptidic benzimidazoles, quorum sensing (QS) inhibitors, and metal-based antibacterial agents. Full article
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