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13 pages, 1232 KiB

Open AccessArticle

Towards a General Method for Using Cyclotron-Produced Ga68 to Manufacture Clinical and Research Ga68 Tracers

by Ivan E. Wang, Kevin Cheng, Allen F. Brooks, Peter J. H. Scott and Benjamin L. Viglianti

Molecules 2024, 29(22), 5457; https://doi.org/10.3390/molecules29225457 - 19 Nov 2024

Viewed by 466

Abstract

The success of multiple nuclear medicine radiotherapeutics in treating cancer requires an increased supply of companion diagnostic imaging agents radiolabeled with gallium-68. Cyclotron production addresses the need for access to gallium-68 and has been validated for use with commercially produced sterile kits. For [...] Read more.

The success of multiple nuclear medicine radiotherapeutics in treating cancer requires an increased supply of companion diagnostic imaging agents radiolabeled with gallium-68. Cyclotron production addresses the need for access to gallium-68 and has been validated for use with commercially produced sterile kits. For novel research tracers undergoing translational studies (IND or RDRC), developing and purchasing sterile kits is time- and cost-prohibitive. An on-cassette labeling method with terminal filtration allows non-sterile kits to be fabricated in-house, simplifying workflow and allowing multiple PET imaging agents to be evaluated using the same kit (i.e., parts, reagents, and timelist) with minimal variation. Using modified GE gallium chloride cassettes, four diverse clinically relevant tracers (DOTA-TOC, FAPI-04, pentixafor, and PSMA-11) were radiolabeled with gallium-68 to evaluate the approach using DOTA and HBED-CC chelator types. The tracers were all formulated according to established FDA-approved formulations and sterile-filtered using a PVDF membrane. The automated procedure is robust, tolerating DOTA and HBED-CC chelators, and can be used to screen numerous gallium-68 agents for rapid translation to clinical use. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)

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22 pages, 3296 KiB

Open AccessArticle

Regioselective Synthesis of Potential Non-Quinonoid Prodrugs of Plasmodione: Antiparasitic Properties Against Two Hemoglobin-Feeding Parasites and Drug Metabolism Studies

by Elena Cesar-Rodo, Baptiste Dupouy, Cécile Häberli, Jean-Marc Strub, David L. Williams, Pascal Mäser, Matthias Rottmann, Jennifer Keiser, Don Antoine Lanfranchi and Elisabeth Davioud-Charvet

Molecules 2024, 29(22), 5268; https://doi.org/10.3390/molecules29225268 - 7 Nov 2024

Viewed by 746

Abstract

Ψ-1,4-naphthoquinones (Ψ-NQ) are non-quinoid compounds in which aromaticity—found in 1,4-naphthoquinones—is broken by the introduction of an angular methyl at C-4a or -8a. This series was designed to act as prodrugs of 1,4-naphthoquinones in an oxidative environment. Furthermore, from a medicinal chemistry point of [...] Read more.

Ψ-1,4-naphthoquinones (Ψ-NQ) are non-quinoid compounds in which aromaticity—found in 1,4-naphthoquinones—is broken by the introduction of an angular methyl at C-4a or -8a. This series was designed to act as prodrugs of 1,4-naphthoquinones in an oxidative environment. Furthermore, from a medicinal chemistry point of view, the loss of planarity of the scaffold might lead to an improved solubility and circumvent the bad reputation of quinones in the pharmaceutical industry. In this work, we illustrated the concept by the synthesis of Ψ -plasmodione regioisomers as prodrugs of the antimalarial plasmodione. The presence of a chiral center introduces a new degree of freedom to be controlled by enantioselectivity and regioselectivity of the cycloaddition in the Diels–Alder reaction. The first strategy that was followed was based on the use of a chiral enantiopure sulfoxide to govern the stereoselective formation of (+)Ψ-NQ or (−)Ψ-NQ, depending on the chirality of the sulfoxide (R or S). New sulfinylquinones were synthesized but were found to be ineffective in undergoing cycloaddition with different dienes under a wide range of conditions (thermal, Lewis acid). The second strategy was based on the use of boronic acid-substituted benzoquinones as auxiliaries to control the regioselectivity. Using this methodology to prepare the (±)Ψ-NQ racemates, promising results (very fast cycloaddition time: ~2 h) were obtained with boronic acid-based quinones 25 and 27 in the presence of 1-methoxy-1,3-butadiene, to generate the 4a- and the 8a-Ψ-plasmodione regioisomers 1 and 2 (synthesized in six steps with a total yield of 10.5% and 4.1%, respectively. As the expected prodrug effect can only be revealed if the molecule undergoes an oxidation of the angular methyl, e.g., in blood-feeding parasites that digest hemoglobin from the host, the antimalarial and the antischistosomal properties of both (±)Ψ-NQ regioisomers were determined in drug assays with Plasmodium falciparum and Schistosoma mansoni. Metabolic studies under quasi-physiological conditions and LC-MS analyses were undertaken to reveal the generation of plasmodione from both the 4a- and the 8a-Ψ-plasmodione regioisomers. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)

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18 pages, 2373 KiB

Open AccessArticle

Identification of a New Promising BAG3 Modulator Featuring the Imidazopyridine Scaffold

by Dafne Ruggiero, Emis Ingenito, Eleonora Boccia, Vincenzo Vestuto, Maria Rosaria Miranda, Stefania Terracciano, Gianluigi Lauro, Giuseppe Bifulco and Ines Bruno

Molecules 2024, 29(21), 5051; https://doi.org/10.3390/molecules29215051 - 25 Oct 2024

Viewed by 651

Abstract

The antiapoptotic BAG3 protein plays a crucial role in cellular proteostasis and it is involved in several signalling pathways governing cell proliferation and survival. Owing to its multimodular structure, it possesses an extensive interactome including the molecular chaperone HSP70 and other specific cellular [...] Read more.

The antiapoptotic BAG3 protein plays a crucial role in cellular proteostasis and it is involved in several signalling pathways governing cell proliferation and survival. Owing to its multimodular structure, it possesses an extensive interactome including the molecular chaperone HSP70 and other specific cellular partners, which make it an eminent factor in several pathologies, particularly in cancer. Despite its potential as a therapeutic target, very few BAG3 modulators have been disclosed so far. Here we describe the identification of a promising BAG3 modulator able to bind the BAG domain of the protein featuring an imidazopyridine scaffold and obtained through the application of the Groebke–Blackburn–Bienaymé chemical synthesis procedure. The disclosed compound 10 showed a relevant cytotoxic activity, and in line with the biological profile of BAG3 disruption, it induced the activation of caspase 3 and 9. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)

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17 pages, 3711 KiB

Open AccessArticle

A Combined Computational and Experimental Approach to Studying Tropomyosin Kinase Receptor B Binders for Potential Treatment of Neurodegenerative Diseases

by Duc D. Nguyen, Shomit Mansur, Lukasz Ciesla, Nora E. Gray, Shan Zhao and Yuping Bao

Molecules 2024, 29(17), 3992; https://doi.org/10.3390/molecules29173992 - 23 Aug 2024

Viewed by 737

Abstract

Tropomyosin kinase receptor B (TrkB) has been explored as a therapeutic target for neurological and psychiatric disorders. However, the development of TrkB agonists was hindered by our poor understanding of the TrkB agonist binding location and affinity (both affect the regulation of disorder [...] Read more.

Tropomyosin kinase receptor B (TrkB) has been explored as a therapeutic target for neurological and psychiatric disorders. However, the development of TrkB agonists was hindered by our poor understanding of the TrkB agonist binding location and affinity (both affect the regulation of disorder types). This motivated us to develop a combined computational and experimental approach to study TrkB binders. First, we developed a docking method to simulate the binding affinity of TrkB and binders identified by our magnetic drug screening platform from Gotu kola extracts. The Fred Docking scores from the docking computation showed strong agreement with the experimental results. Subsequently, using this screening platform, we identified a list of compounds from the NIH clinical collection library and applied the same docking studies. From the Fred Docking scores, we selected two compounds for TrkB activation tests. Interestingly, the ability of the compounds to increase dendritic arborization in hippocampal neurons matched well with the computational results. Finally, we performed a detailed binding analysis of the top candidates and compared them with the best-characterized TrkB agonist, 7,8-dyhydroxyflavon. The screening platform directly identifies TrkB binders, and the computational approach allows for the quick selection of top candidates with potential biological activities based on the docking scores. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)

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19 pages, 9295 KiB

Open AccessArticle

A New Class of Benzo[b]thiophene-chalcones as Cholinesterase Inhibitors: Synthesis, Biological Evaluation, Molecular Docking and ADME Studies

by Giovanna Lucia Delogu, Michela Begala, Maria João Matos, Davide Crucitti, Valeria Sogos, Benedetta Era and Antonella Fais

Molecules 2024, 29(16), 3748; https://doi.org/10.3390/molecules29163748 - 7 Aug 2024

Viewed by 1490

Abstract

In this study, heterocyclic compounds containing a benzothiophene scaffold were designed and synthetized, and their inhibitory activity against cholinesterases (ChE) and the viability of SH-SY5Y cells have been evaluated. Benzothiophenes 4a–4i and benzothiophene-chalcone hybrids 5a–5i were tested against both [...] Read more.

In this study, heterocyclic compounds containing a benzothiophene scaffold were designed and synthetized, and their inhibitory activity against cholinesterases (ChE) and the viability of SH-SY5Y cells have been evaluated. Benzothiophenes 4a–4i and benzothiophene-chalcone hybrids 5a–5i were tested against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing interesting structure–activity relationships. In general, benzothiophene–chalcone hybrids from series 5 proved to be better inhibitors of both enzymes, with compound 5f being the best AChE inhibitor (IC₅₀ = 62.10 μM) and compound 5h being the best BChE inhibitor (IC₅₀ = 24.35 μM), the last one having an IC₅₀ similar to that of galantamine (IC₅₀ = 28.08 μM), the reference compound. The in silico ADME profile of the compounds was also studied. Molecular docking calculations were carried out to analyze the best binding scores and to elucidate enzyme–inhibitors’ interactions. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)

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17 pages, 1077 KiB

Open AccessArticle

Investigations of Antioxidant and Anti-Cancer Activities of 5-Aminopyrazole Derivatives

by Federica Rapetti, Andrea Spallarossa, Eleonora Russo, Debora Caviglia, Carla Villa, Bruno Tasso, Maria Grazia Signorello, Camillo Rosano, Erika Iervasi, Marco Ponassi and Chiara Brullo

Molecules 2024, 29(10), 2298; https://doi.org/10.3390/molecules29102298 - 14 May 2024

Cited by 1 | Viewed by 967

Abstract

To further extend the structure-activity relationships (SARs) of 5-aminopyrazoles (5APs) and identify novel compounds able to interfere with inflammation, oxidative stress, and tumorigenesis, 5APs 1–4 have been designed and prepared. Some chemical modifications have been inserted on cathecol function or in aminopyrazole central [...] Read more.

To further extend the structure-activity relationships (SARs) of 5-aminopyrazoles (5APs) and identify novel compounds able to interfere with inflammation, oxidative stress, and tumorigenesis, 5APs 1–4 have been designed and prepared. Some chemical modifications have been inserted on cathecol function or in aminopyrazole central core; in detail: (i) smaller, bigger, and more lipophilic substituents were introduced in meta and para positions of catechol portion (5APs 1); (ii) a methyl group was inserted on C3 of the pyrazole scaffold (5APs 2); (iii) a more flexible alkyl chain was inserted on N1 position (5APs 3); (iv) the acylhydrazonic linker was moved from position 4 to position 3 of the pyrazole scaffold (5APs 4). All new derivatives 1–4 have been tested for radical scavenging (DPPH assay), anti-aggregating/antioxidant (in human platelets) and cell growth inhibitory activity (MTT assay) properties. In addition, in silico pharmacokinetics, drug-likeness properties, and toxicity have been calculated. 5APs 1 emerged to be promising anti-proliferative agents, able to suppress the growth of specific cancer cell lines. Furthermore, derivatives 3 remarkably inhibited ROS production in platelets and 5APs 4 showed interesting in vitro radical scavenging properties. Overall, the collected results further confirm the pharmaceutical potentials of this class of compounds and support future studies for the development of novel anti-proliferative and antioxidant agents. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)

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20 pages, 1845 KiB

Open AccessArticle

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 990

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

Open AccessArticle

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

Cited by 5 | Viewed by 2495

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

Open AccessArticle

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 - 4 Nov 2023

Viewed by 1802

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

Open AccessArticle

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 4 | Viewed by 1310

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

Open AccessArticle

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

Cited by 1 | Viewed by 1789

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

Open AccessArticle

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

Cited by 2 | Viewed by 1661

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

Open AccessArticle

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 2 | Viewed by 2426

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 10r–s 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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27 pages, 3285 KiB

Open AccessReview

Orthoflaviviral Inhibitors in Clinical Trials, Preclinical In Vivo Efficacy Targeting NS2B-NS3 and Cellular Antiviral Activity via Competitive Protease Inhibition

by Lorenzo Cavina, Mathijs J. Bouma, Daniel Gironés and Martin C. Feiters

Molecules 2024, 29(17), 4047; https://doi.org/10.3390/molecules29174047 - 27 Aug 2024

Viewed by 1343

Abstract

Orthoflaviviruses, including zika (ZIKV), West Nile (WNV), and dengue (DENV) virus, induce severely debilitating infections and contribute significantly to the global disease burden, yet no clinically approved antiviral treatments exist. This review offers a comprehensive analysis of small-molecule drug development targeting orthoflaviviral infections, [...] Read more.

Orthoflaviviruses, including zika (ZIKV), West Nile (WNV), and dengue (DENV) virus, induce severely debilitating infections and contribute significantly to the global disease burden, yet no clinically approved antiviral treatments exist. This review offers a comprehensive analysis of small-molecule drug development targeting orthoflaviviral infections, with a focus on NS2B-NS3 inhibition. We systematically examined clinical trials, preclinical efficacy studies, and modes of action for various viral replication inhibitors, emphasizing allosteric and orthosteric drugs inhibiting NS2B-NS3 protease with in vivo efficacy and in vitro-tested competitive NS2B-NS3 inhibitors with cellular efficacy. Our findings revealed that several compounds with in vivo preclinical efficacy failed to show clinical antiviral efficacy. NS3-NS4B inhibitors, such as JNJ-64281802 and EYU688, show promise, recently entering clinical trials, underscoring the importance of developing novel viral replication inhibitors targeting viral machinery. To date, the only NS2B-NS3 inhibitor that has undergone clinical trials is doxycycline, however, its mechanism of action and clinical efficacy as viral growth inhibitor require additional investigation. SYC-1307, an allosteric inhibitor, exhibits high in vivo efficacy, while temoporfin and methylene blue represent promising orthosteric non-competitive inhibitors. Compound 71, a competitive NS2B-NS3 inhibitor, emerges as a leading preclinical candidate due to its high cellular antiviral efficacy, minimal cytotoxicity, and favorable in vitro pharmacokinetic parameters. Challenges remain in developing competitive NS2B-NS3 inhibitors, including appropriate biochemical inhibition assays as well as the selectivity and conformational flexibility of the protease, complicating effective antiviral treatment design. Full article

(This article belongs to the Special Issue Featured Papers in Medicinal Chemistry II)

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24 pages, 3468 KiB

Open AccessReview

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 9 | Viewed by 5739

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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