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Featured Papers in Medicinal Chemistry II

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

Deadline for manuscript submissions: 31 July 2024 | Viewed by 11383

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
Special Issues, Collections and Topics in MDPI journals
School of Pharmacy, University of Reading, Reading, UK
Interests: development of new chemical and enzymatic methods for the treatment of life threatening diseases; anti-infective agent; glycosidase enzyme inhibitors; anti-viral agents; personalised medicines
Special Issues, Collections and Topics in MDPI journals
Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677, USA
Interests: computational medicinal chemistry; cannabinoid receptors; drug discovery; quantum chemistry; allosteric modulators; protein modeling; quantitative structure–activity relationships
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to announce the second edition of Special Issue entitled "Featured Papers in Medicinal Chemistry". This is a collection of important high-quality papers (original research articles or comprehensive review papers) published in open access format by Editorial Board Members or prominent scholars invited by the Editorial Office and the Guest Editors. This Special Issue aims to discuss new knowledge or new cutting-edge developments in the medicinal chemistry research field through selected works, in the hope of making a great contribution to the community. We intend for this issue to be the best forum for disseminating excellent research findings as well as sharing innovative ideas in the field. Please, feel free to contact Cecilia Li (cecilia.li@mdpi.com) if you would like to contribute to this Special Issue.

Dr. Diego Muñoz-Torrero
Prof. Dr. Helen Osborn
Dr. Robert J. Doerksen
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 (8 papers)

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Research

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20 pages, 1845 KiB  
Article
Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived Cyclolignan
by Pablo A. García, Ángela-Patricia Hernández, Mª Antonia Gómez-Zurita, José M. Miguel del Corral, Marina Gordaliza, Andrés Francesch, Arturo San Feliciano and Mª Ángeles Castro
Molecules 2024, 29(7), 1442; https://doi.org/10.3390/molecules29071442 - 23 Mar 2024
Viewed by 268
Abstract
Podophyllotoxin, a cyclolignan natural product, has been the object of extensive chemomodulation to obtain better chemotherapeutic agents. Among the obtained podophyllotoxin derivatives, podophyllic aldehyde showed very interesting potency and selectivity against several tumoral cell lines, so it became our lead compound for further [...] Read more.
Podophyllotoxin, a cyclolignan natural product, has been the object of extensive chemomodulation to obtain better chemotherapeutic agents. Among the obtained podophyllotoxin derivatives, podophyllic aldehyde showed very interesting potency and selectivity against several tumoral cell lines, so it became our lead compound for further modifications, as described in this work, oriented toward the enlargement of the cyclolignan skeleton. Thus, modifications performed at the aldehyde function included nucleophilic addition reactions and the incorporation of the aldehyde carbon into several five-membered rings, such as thiazolidinones and benzo-fused azoles. The synthesized derivatives were evaluated against several types of cancer cells, and although some compounds were cytotoxic at the nanomolar range, most of them were less potent and less selective than the parent compound podophyllic aldehyde, with the most potent being those having the lactone ring of podophyllotoxin. In silico ADME evaluation predicted good druggability for most of them. The results indicate that the γ-lactone ring is important for potency, while the α,β-unsaturated aldehyde is necessary to induce selectivity in these cyclolignans. Full article
(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)
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14 pages, 3763 KiB  
Article
Synergistic Effects of Temozolomide and Doxorubicin in the Treatment of Glioblastoma Multiforme: Enhancing Efficacy through Combination Therapy
by Laxmi Dhungel, Mandy E. Rowsey, Cayla Harris and Drazen Raucher
Molecules 2024, 29(4), 840; https://doi.org/10.3390/molecules29040840 - 14 Feb 2024
Viewed by 708
Abstract
Glioblastoma multiforme (GBM), a grade IV (WHO classification) malignant brain tumor, poses significant challenges in treatment. The current standard treatment involves surgical tumor removal followed by radiation and chemotherapeutic interventions. However, despite these efforts, the median survival for GBM patients remains low. Temozolomide, [...] Read more.
Glioblastoma multiforme (GBM), a grade IV (WHO classification) malignant brain tumor, poses significant challenges in treatment. The current standard treatment involves surgical tumor removal followed by radiation and chemotherapeutic interventions. However, despite these efforts, the median survival for GBM patients remains low. Temozolomide, an alkylating agent capable of crossing the blood–brain barrier, is currently the primary drug for GBM treatment. Its efficacy, however, is limited, leading to the exploration of combination treatments. In this study, we have investigated the synergistic effects of combining temozolomide with doxorubicin, a chemotherapeutic agent widely used against various cancers. Our experiments, conducted on both temozolomide-sensitive (U87) and -resistant cells (GBM43 and GBM6), have demonstrated a synergistic inhibition of brain cancer cells with this combination treatment. Notably, the combination enhanced doxorubicin uptake and induced higher apoptosis in temozolomide-resistant GBM43 cells. The significance of our findings lies in the potential application of this combination treatment, even in cases of temozolomide resistance. Despite doxorubicin’s inability to cross the blood–brain barrier, our results open avenues for alternative delivery methods, such as conjugation with carriers like albumin or local administration at the surgical site through a hydrogel application system. Our study suggests that the synergistic interaction between temozolomide and doxorubicin holds promise for enhancing the efficacy of glioblastoma treatment. The positive outcomes observed in our experiments provide confidence in considering this strategy for the benefit of patients with glioblastoma. Full article
(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)
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20 pages, 3484 KiB  
Article
Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets
by Filippo Basagni, Maria Luisa Di Paolo, Giorgio Cozza, Lisa Dalla Via, Francesca Fagiani, Cristina Lanni, Michela Rosini and Anna Minarini
Molecules 2023, 28(21), 7424; https://doi.org/10.3390/molecules28217424 - 04 Nov 2023
Viewed by 1065
Abstract
Oxidative stress and neuroinflammation play a pivotal role in triggering the neurodegenerative pathological cascades which characterize neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. In search for potential efficient treatments for these pathologies, that are still considered unmet medical needs, we started from [...] Read more.
Oxidative stress and neuroinflammation play a pivotal role in triggering the neurodegenerative pathological cascades which characterize neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. In search for potential efficient treatments for these pathologies, that are still considered unmet medical needs, we started from the promising properties of the antidiabetic drug pioglitazone, which has been repositioned as an MAO-B inhibitor, characterized by promising neuroprotective properties. Herein, with the aim to broaden its neuroprotective profile, we tried to enrich pioglitazone with direct and indirect antioxidant properties by hanging polyphenolic and electrophilic features that are able to trigger Nrf2 pathway and the resulting cytoprotective genes’ transcription, as well as serve as radical scavengers. After a preliminary screening on MAO-B inhibitory properties, caffeic acid derivative 2 emerged as the best inhibitor for potency and selectivity over MAO-A, characterized by a reversible mechanism of inhibition. Furthermore, the same compound proved to activate Nrf2 pathway by potently increasing Nrf2 nuclear translocation and strongly reducing ROS content, both in physiological and stressed conditions. Although further biological investigations are required to fully clarify its neuroprotective properties, we were able to endow the pioglitazone scaffold with potent antioxidant properties, representing the starting point for potential future pioglitazone-based therapeutics for neurodegenerative disorders. Full article
(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)
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18 pages, 2574 KiB  
Article
m-Terphenylamines, Acting as Selective COX-1 Inhibitors, Block Microglia Inflammatory Response and Exert Neuroprotective Activity
by Damiano Rocchi, Juan F. González, Olmo Martín-Cámara, Maria Grazia Perrone, Morena Miciaccia, Antonio Scilimati, Celine Decouty-Pérez, Esther Parada, Javier Egea and J. Carlos Menéndez
Molecules 2023, 28(14), 5374; https://doi.org/10.3390/molecules28145374 - 13 Jul 2023
Cited by 2 | Viewed by 749
Abstract
Inhibition of cyclooxygenase-2 (COX-2) has been extensively studied as an approach to reduce proinflammatory markers in acute brain diseases, but the anti-neuroinflammatory role of cyclooxygenase-1 (COX-1) inhibition has been rather neglected. We report that m-terphenylamine derivatives are selective COX-1 inhibitors, able to [...] Read more.
Inhibition of cyclooxygenase-2 (COX-2) has been extensively studied as an approach to reduce proinflammatory markers in acute brain diseases, but the anti-neuroinflammatory role of cyclooxygenase-1 (COX-1) inhibition has been rather neglected. We report that m-terphenylamine derivatives are selective COX-1 inhibitors, able to block microglia inflammatory response and elicit a neuroprotective effect. These compounds were synthesized via a three-component reaction of chalcones, β-ketoesters, and primary amines, followed by hydrolysis/decarboxylation of the ester group. Together with their synthetic intermediates and some urea derivatives, they were studied as inhibitors of COX-1 and COX-2. The m-terphenylamine derivatives, which were selective COX-1 inhibitors, were also analyzed for their ability to block microglia inflammatory and oxidative response. Compound 3b presented an interesting anti-inflammatory and neuroprotective profile by reducing nitrite release, ROS overproduction, and cell death in organotypic hippocampal cultures subjected to LPS. We thus show that COX-1 inhibition is a promising approach to provide enhanced neuroprotection against acute inflammatory processes, which are crucial in the development of a plethora of acute neurodegenerative injuries. Full article
(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)
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14 pages, 2561 KiB  
Article
Fluorine-Functionalized Polyphosphazene Immunoadjuvant: Synthesis, Solution Behavior and In Vivo Potency
by Harichandra D. Tagad, Alexander Marin, Ruixue Wang, Abdul S. Yunus, Thomas R. Fuerst and Alexander K. Andrianov
Molecules 2023, 28(10), 4218; https://doi.org/10.3390/molecules28104218 - 21 May 2023
Viewed by 1252
Abstract
The inclusion of fluorine motifs in drugs and drug delivery systems is an established tool for modulating their biological potency. Fluorination can improve drug specificity or boost the vehicle’s ability to cross cellular membranes. However, the approach has yet to be applied to [...] Read more.
The inclusion of fluorine motifs in drugs and drug delivery systems is an established tool for modulating their biological potency. Fluorination can improve drug specificity or boost the vehicle’s ability to cross cellular membranes. However, the approach has yet to be applied to vaccine adjuvants. Herein, the synthesis of fluorinated bioisostere of a clinical stage immunoadjuvant—poly[di(carboxylatophenoxy)phosphazene], PCPP—is reported. The structure of water-soluble fluoropolymer—PCPP-F, which contains two fluorine atoms per repeat unit—was confirmed using 1H, 31P and 19F NMR, and its molecular mass and molecular dimensions were determined using size-exclusion chromatography and dynamic light scattering. Insertion of fluorine atoms in the polymer side group resulted in an improved solubility in acidic solutions and faster hydrolytic degradation rate, while the ability to self-assemble with an antigenic protein, lysozyme—an important feature of polyphosphazene vaccine adjuvants—was preserved. In vivo assessment of PCPP-F demonstrated its greater ability to induce antibody responses to Hepatitis C virus antigen when compared to its non-fluorinated counterpart. Taken together, the superior immunoadjuvant activity of PCPP-F, along with its improved formulation characteristics, demonstrate advantages of the fluorination approach for the development of this family of macromolecular vaccine adjuvants. Full article
(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)
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24 pages, 5513 KiB  
Article
Tetrasubstituted Pyrrole Derivative Mimetics of Protein–Protein Interaction Hot-Spot Residues: A Promising Class of Anticancer Agents Targeting Melanoma Cells
by Marco Persico, Paola Galatello, Maria Grazia Ferraro, Carlo Irace, Marialuisa Piccolo, Avazbek Abduvakhidov, Oleh Tkachuk, Maria Luisa d’Aulisio Garigliota, Pietro Campiglia, Patrizia Iannece, Michela Varra, Anna Ramunno and Caterina Fattorusso
Molecules 2023, 28(10), 4161; https://doi.org/10.3390/molecules28104161 - 18 May 2023
Viewed by 1162
Abstract
A new series of tetrasubstituted pyrrole derivatives (TSPs) was synthesized based on a previously developed hypothesis on their ability to mimic hydrophobic protein motifs. The resulting new TSPs were endowed with a significant toxicity against human epithelial melanoma A375 cells, showing IC50 [...] Read more.
A new series of tetrasubstituted pyrrole derivatives (TSPs) was synthesized based on a previously developed hypothesis on their ability to mimic hydrophobic protein motifs. The resulting new TSPs were endowed with a significant toxicity against human epithelial melanoma A375 cells, showing IC50 values ranging from 10 to 27 μM, consistent with the IC50 value of the reference compound nutlin-3a (IC50 = 15 μM). In particular, compound 10a (IC50 = 10 μM) resulted as both the most soluble and active among the previous and present TSPs. The biological investigation evidenced that the anticancer activity is related to the activation of apoptotic cell-death pathways, supporting our rational design based on the ability of TSPs to interfere with PPI involved in the cell cycle regulation of cancer cells and, in particular, the p53 pathway. A reinvestigation of the TSP pharmacophore by using DFT calculations showed that the three aromatic substituents on the pyrrole core are able to mimic the hydrophobic side chains of the hot-spot residues of parallel and antiparallel coiled coil structures suggesting a possible molecular mechanism of action. A structure–activity relationship (SAR) analysis which includes solubility studies allows us to rationalize the role of the different substituents on the pyrrole core. Full article
(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)
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39 pages, 5408 KiB  
Article
Synthesis and In Vitro Antimicrobial SAR of Benzyl and Phenyl Guanidine and Aminoguanidine Hydrazone Derivatives
by Wolfgang Dohle, Xiangdong Su, Yamni Nigam, Edward Dudley and Barry V. L. Potter
Molecules 2023, 28(1), 5; https://doi.org/10.3390/molecules28010005 - 20 Dec 2022
Cited by 1 | Viewed by 1611
Abstract
A series of benzyl, phenyl guanidine, and aminoguandine hydrazone derivatives was designed and in vitro antibacterial activities against two different bacterial strains (Staphylococcus aureus and Escherichia coli) were determined. Several compounds showed potent inhibitory activity against the bacterial strains evaluated, with [...] Read more.
A series of benzyl, phenyl guanidine, and aminoguandine hydrazone derivatives was designed and in vitro antibacterial activities against two different bacterial strains (Staphylococcus aureus and Escherichia coli) were determined. Several compounds showed potent inhibitory activity against the bacterial strains evaluated, with minimal inhibitory concentration (MIC) values in the low µg/mL range. Of all guanidine derivatives, 3-[2-chloro-3-(trifluoromethyl)]-benzyloxy derivative 9m showed the best potency with MICs of 0.5 µg/mL (S. aureus) and 1 µg/mL (E. coli), respectively. Several aminoguanidine hydrazone derivatives also showed good overall activity. Compounds 10a, 10j, and 10rs displayed MICs of 4 µg/mL against both S. aureus and E. coli. In the aminoguanidine hydrazone series, 3-(4-trifluoromethyl)-benzyloxy derivative 10d showed the best potency against S. aureus (MIC 1 µg/mL) but was far less active against E. coli (MIC 16 µg/mL). Compound 9m and the para-substituted derivative 9v also showed promising results against two strains of methicillin-resistant Staphylococcus aureus (MRSA). These results provide new and potent structural leads for further antibiotic optimisation strategies. Full article
(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)
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Review

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24 pages, 3468 KiB  
Review
Asymmetric Organocatalysis: A Survival Guide to Medicinal Chemists
by Efraim Reyes, Liher Prieto and Andrea Milelli
Molecules 2023, 28(1), 271; https://doi.org/10.3390/molecules28010271 - 29 Dec 2022
Cited by 2 | Viewed by 3679
Abstract
Majority of drugs act by interacting with chiral counterparts, e.g., proteins, and we are, unfortunately, well-aware of how chirality can negatively impact the outcome of a therapeutic regime. The number of chiral, non-racemic drugs on the market is increasing, and it is becoming [...] Read more.
Majority of drugs act by interacting with chiral counterparts, e.g., proteins, and we are, unfortunately, well-aware of how chirality can negatively impact the outcome of a therapeutic regime. The number of chiral, non-racemic drugs on the market is increasing, and it is becoming ever more important to prepare these compounds in a safe, economic, and environmentally sustainable fashion. Asymmetric organocatalysis has a long history, but it began its renaissance era only during the first years of the millennium. Since then, this field has reached an extraordinary level, as confirmed by the awarding of the 2021 Chemistry Nobel Prize. In the present review, we wish to highlight the application of organocatalysis in the synthesis of enantio-enriched molecules that may be of interest to the pharmaceutical industry and the medicinal chemistry community. We aim to discuss the different activation modes observed for organocatalysts, examining, for each of them, the generally accepted mechanisms and the most important and developed reactions, that may be useful to medicinal chemists. For each of these types of organocatalytic activations, select examples from academic and industrial applications will be disclosed during the synthesis of drugs and natural products. Full article
(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)
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