Molecules

11 pages, 7990 KiB

Open AccessArticle

Synthesis and Biochemical Evaluation of 8H-Indeno[1,2-d]thiazole Derivatives as Novel SARS-CoV-2 3CL Protease Inhibitors

by Jing Wu, Bo Feng, Li-Xin Gao, Chun Zhang, Jia Li, Da-Jun Xiang, Yi Zang and Wen-Long Wang

Molecules 2022, 27(10), 3359; https://doi.org/10.3390/molecules27103359 - 23 May 2022

Cited by 3 | Viewed by 2466

Abstract

The COVID-19 pandemic caused by SARS-CoV-2 is a global burden on human health and economy. The 3-Chymotrypsin-like cysteine protease (3CL^pro) becomes an attractive target for SARS-CoV-2 due to its important role in viral replication. We synthesized a series of 8H [...] Read more.

The COVID-19 pandemic caused by SARS-CoV-2 is a global burden on human health and economy. The 3-Chymotrypsin-like cysteine protease (3CL^pro) becomes an attractive target for SARS-CoV-2 due to its important role in viral replication. We synthesized a series of 8H-indeno[1,2-d]thiazole derivatives and evaluated their biochemical activities against SARS-CoV-2 3CL^pro. Among them, the representative compound 7a displayed inhibitory activity with an IC₅₀ of 1.28 ± 0.17 μM against SARS-CoV-2 3CL^pro. Molecular docking of 7a against 3CL^pro was performed and the binding mode was rationalized. These preliminary results provide a unique prototype for the development of novel inhibitors against SARS-CoV-2 3CL^pro. Full article

(This article belongs to the Special Issue Synthesis of Heteroaromatic Compounds)

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20 pages, 2385 KiB

Open AccessArticle

Elucidation of the Lipid Composition of Hemp (Cannabis sativa L.) Products by Means of Gas Chromatography and Ultra-High Performance Liquid Chromatography Coupled to Mass Spectrometry Detection

by Paola Arena, Francesca Rigano, Paolo Guarnaccia, Paola Dugo, Luigi Mondello and Emanuela Trovato

Molecules 2022, 27(10), 3358; https://doi.org/10.3390/molecules27103358 - 23 May 2022

Cited by 16 | Viewed by 3138

Abstract

The growing demand in natural matrices that represent a source of dietary and nutraceutical molecules has led to an increasing interest in Cannabis sativa, considered to be a multipurpose, sustainable crop. Particularly, the considerable content in essential fatty acids (FAs) makes its [...] Read more.

The growing demand in natural matrices that represent a source of dietary and nutraceutical molecules has led to an increasing interest in Cannabis sativa, considered to be a multipurpose, sustainable crop. Particularly, the considerable content in essential fatty acids (FAs) makes its derived-products useful food ingredients in the formulation of dietary supplements. In this research, the FA and triacylglycerol (TAG) composition of hempseed oils and flours were investigated using gas chromatography coupled to mass spectrometry and flame ionization detection as well as liquid chromatography coupled to mass spectrometry (LC-MS), respectively. Furthermore, a recently introduced linear retention index (LRI) approach in LC was successfully employed as a useful tool for the reliable identification of TAG species. A total of 30 FAs and 62 glycerolipids were positively identified in the investigated samples. Relative quantitative analyses confirmed linoleic acid as the most abundant component (50–55%). A favorable omega6/omega3 ratio was also measured in hemp-derived products, with the α-linolenic acid around 12–14%. Whereas, γ-linolenic acid was found to be higher than 1.70%. These results confirm the great value of Cannabis sativa as a source of valuable lipids, and the further improvement of the LRI system paves the way for the automatization of the identification process in LC. Full article

(This article belongs to the Special Issue Isolation, Identification and Bioactivity of Food-Derived Compounds)

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17 pages, 1541 KiB

Open AccessArticle

The Effect of Standardised Leaf Extracts of Gaultheria procumbens on Multiple Oxidants, Inflammation-Related Enzymes, and Pro-Oxidant and Pro-Inflammatory Functions of Human Neutrophils

by Piotr Michel, Sebastian Granica, Karolina Rosińska, Małgorzata Glige, Jarosław Rojek, Łukasz Poraj and Monika Anna Olszewska

Molecules 2022, 27(10), 3357; https://doi.org/10.3390/molecules27103357 - 23 May 2022

Cited by 10 | Viewed by 2681

Abstract

The leaves of Gaultheria procumbens are polyphenol-rich traditional medicines used to treat inflammation-related diseases. The present study aimed to optimise the solvent for the effective recovery of active leaf components through simple direct extraction and verify the biological effects of the selected extract [...] Read more.

The leaves of Gaultheria procumbens are polyphenol-rich traditional medicines used to treat inflammation-related diseases. The present study aimed to optimise the solvent for the effective recovery of active leaf components through simple direct extraction and verify the biological effects of the selected extract in a model of human neutrophils ex vivo. The extracts were comprehensively standardised, and forty-one individual polyphenols, representing salicylates, catechins, procyanidins, phenolic acids, and flavonoids, were identified by UHPLC–PDA–ESI–MS³. The chosen methanol–water (75:25, v/v) extract (ME) was obtained with the highest extraction yield and total phenolic levels (397.9 mg/g extract’s dw), including 98.9 mg/g salicylates and 299.0 mg/g non-salicylate polyphenols. In biological tests, ME revealed a significant and dose-dependent ability to modulate pro-oxidant and pro-inflammatory functions of human neutrophils: it strongly reduced the ROS level and downregulated the release of pro-inflammatory cytokines and tissue remodelling enzymes, especially IL-1β and elastase 2, in cells stimulated by fMLP, LPS, or fMLP + cytochalasin B. The extracts were also potent direct scavengers of in vivo relevant oxidants (O₂^•−, ^•OH, and H₂O₂) and inhibitors of pro-inflammatory enzymes (cyclooxygenase-2, hyaluronidase, and lipoxygenase). The statistically significant correlations between the tested variables revealed the synergic contribution of individual polyphenols to the observed effects and indicated them as useful active markers for the standardisation of the extract/plant material. Moreover, the safety of ME was confirmed in cytotoxicity tests. The obtained results might partially explain the ethnomedicinal application of G. procumbens leaves and support the usage of the standardised leaf extract in the adjuvant treatment of oxidative stress and inflammation-related chronic diseases. Full article

(This article belongs to the Special Issue Phytochemistry and Biological Properties of Medicinal Plants)

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14 pages, 1294 KiB

Open AccessArticle

Determination of Glycerophospholipids in Biological Material Using High-Performance Liquid Chromatography with Charged Aerosol Detector HPLC-CAD—A New Approach for Isolation and Quantification

by Magdalena Rosłon, Małgorzata Jaworska and Elżbieta L. Anuszewska

Molecules 2022, 27(10), 3356; https://doi.org/10.3390/molecules27103356 - 23 May 2022

Cited by 2 | Viewed by 3392

Abstract

The method of using high-performance liquid chromatography with a charged aerosol detector method (HPLC-CAD) was developed for the separation and determination of phospholipids isolated from cell membranes. The established cell lines—normal and neoplastic prostate cells and normal skin fibroblasts and melanoma cells—were selected [...] Read more.

The method of using high-performance liquid chromatography with a charged aerosol detector method (HPLC-CAD) was developed for the separation and determination of phospholipids isolated from cell membranes. The established cell lines—normal and neoplastic prostate cells and normal skin fibroblasts and melanoma cells—were selected for the study. Chromatographic separation was performed in the diol stationary phase using a gradient elution based on a mixture of n-hexane, isopropanol and water with the addition of triethylamine and acetic acid as buffer additives. Taking the elements of the Folch and Bligh–Dyer methods, an improved procedure for lipid isolation from biological material was devised. Ultrasound-assisted extraction included three extraction steps and changed the composition of the extraction solvent, which led to higher recovery of the tested phospholipids. This method was validated by assessing the analytical range, precision, intermediate precision and accuracy. The analytical range was adjusted to the expected concentrations in cell extracts of various origins (from 40 µg/mL for PS up to 10 mg/mL for PC). Both precision and intermediate precision were at a similar level and ranged from 3.5% to 9.0%. The recovery for all determined phospholipids was found to be between 95% and 110%. The robustness of the method in terms of the use of equivalent columns was also confirmed. Due to the curvilinear response of CAD, the quantification was based on an internal standard method combined with a power function transformation of the normalized peak areas, allowing the linearization of the signal with an R² greater than 0.996. The developed method was applied for the isolation and determination of glycerophospholipids from cell membranes, showing that the profile of the tested substances was characteristic of various types of cells. This method can be used to assess changes in metabolism between normal cells and neoplastic cells or cells with certain pathologies or genetic changes. Full article

(This article belongs to the Special Issue Applications of Chromatographic Techniques in Biological, Food and Environmental Samples)

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13 pages, 1938 KiB

Open AccessArticle

Utilization of Phyllanthus emblica fruit stone as a Potential Biomaterial for Sustainable Remediation of Lead and Cadmium Ions from Aqueous Solutions

by Sarita Kushwaha, Suhas, Monika Chaudhary, Inderjeet Tyagi, Rakesh Bhutiani, Joanna Goscianska, Jahangeer Ahmed, Manila and Shubham Chaudhary

Molecules 2022, 27(10), 3355; https://doi.org/10.3390/molecules27103355 - 23 May 2022

Cited by 11 | Viewed by 2657

Abstract

In the present work, an effort has been made to utilize Phyllanthus emblica (PE) fruit stone as a potential biomaterial for the sustainable remediation of noxious heavy metals viz. Pb(II) and Cd(II) from the aqueous solution using adsorption methodology. Further, to elucidate the [...] Read more.

In the present work, an effort has been made to utilize Phyllanthus emblica (PE) fruit stone as a potential biomaterial for the sustainable remediation of noxious heavy metals viz. Pb(II) and Cd(II) from the aqueous solution using adsorption methodology. Further, to elucidate the adsorption potential of Phyllanthus emblica fruit stone (PEFS), effective parameters, such as contact time, initial metal concentration, temperature, etc., were investigated and optimized using a simple batch adsorption method. It was observed that 80% removal for both the heavy metal ions was carried out within 60 min of contact time at an optimized pH 6. Moreover, the thermodynamic parameters results indicated that the adsorption process in the present study was endothermic, spontaneous, and feasible in nature. The positive value of entropy further reflects the high adsorbent–adsorbate interaction. Thus, based on the findings obtained, it can be concluded that the biosorbent may be considered a potential material for the remediation of these noxious impurities and can further be applied or extrapolated to other impurities. Full article

(This article belongs to the Special Issue Emerging Catalytic, Energetic, and Inorganic Nonmetallic Materials)

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10 pages, 642 KiB

Open AccessReview

Immuno-Imaging (PET/SPECT)–Quo Vadis?

by Carsten S. Kramer and Antonia Dimitrakopoulou-Strauss

Molecules 2022, 27(10), 3354; https://doi.org/10.3390/molecules27103354 - 23 May 2022

Cited by 9 | Viewed by 3413

Abstract

The use of immunotherapy has revolutionized the treatment regimen of certain cancer types, but response assessment has become a difficult task with conventional methods such as CT/MRT or FDG PET-CT and the classical response criteria such as RECIST or PERCIST which have been [...] Read more.

The use of immunotherapy has revolutionized the treatment regimen of certain cancer types, but response assessment has become a difficult task with conventional methods such as CT/MRT or FDG PET-CT and the classical response criteria such as RECIST or PERCIST which have been developed for chemotherapeutic treatment. Plenty of new tracers have been published to improve the assessment of treatment response and to stratify the patient population. We gathered the information on published tracers (in total, 106 individual SPECT/PET tracers were identified) and performed a descriptor-based analysis; in this way, we classify the tracers with regard to target choice, developability (probability to progress from preclinical stage into the clinic), translatability (probability to be widely applied in the ‘real world’), and (assumed) diagnostic quality. In our analysis, we show that most tracers are targeting PD-L1, PD-1, CTLA-4, and CD8 receptors by using antibodies or their fragments. Another finding is that plenty of tracers possess only minor iterations regarding chelators and nuclides instead of approaching the problem in a new innovative way. Based on the data, we suggest an orthogonal approach by targeting intracellular targets with PET-activatable small molecules that are currently underrepresented. Full article

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20 pages, 24662 KiB

Open AccessArticle

In Silico Identification of Potential Sites for a Plastic-Degrading Enzyme by a Reverse Screening through the Protein Sequence Space and Molecular Dynamics Simulations

by Krit Charupanit, Varomyalin Tipmanee, Thana Sutthibutpong and Praopim Limsakul

Molecules 2022, 27(10), 3353; https://doi.org/10.3390/molecules27103353 - 23 May 2022

Cited by 10 | Viewed by 4308

Abstract

The accumulation of polyethylene terephthalate (PET) seriously harms the environment because of its high resistance to degradation. The recent discovery of the bacteria-secreted biodegradation enzyme, PETase, sheds light on PET recycling; however, the degradation efficiency is far from practical use. Here, in silico [...] Read more.

The accumulation of polyethylene terephthalate (PET) seriously harms the environment because of its high resistance to degradation. The recent discovery of the bacteria-secreted biodegradation enzyme, PETase, sheds light on PET recycling; however, the degradation efficiency is far from practical use. Here, in silico alanine scanning mutagenesis (ASM) and site-saturation mutagenesis (SSM) were employed to construct the protein sequence space from binding energy of the PETase–PET interaction to identify the number and position of mutation sites and their appropriate side-chain properties that could improve the PETase–PET interaction. The binding mechanisms of the potential PETase variant were investigated through atomistic molecular dynamics simulations. The results show that up to two mutation sites of PETase are preferable for use in protein engineering to enhance the PETase activity, and the proper side chain property depends on the mutation sites. The predicted variants agree well with prior experimental studies. Particularly, the PETase variants with S238C or Q119F could be a potential candidate for improving PETase. Our combination of in silico ASM and SSM could serve as an alternative protocol for protein engineering because of its simplicity and reliability. In addition, our findings could lead to PETase improvement, offering an important contribution towards a sustainable future. Full article

(This article belongs to the Special Issue Virtual Screening in Chemical Biology)

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17 pages, 1280 KiB

Open AccessArticle

Synthesis and Biological Evaluation of 5′-O-Fatty Acyl Ester Derivatives of 3′-Fluoro-2′,3′-dideoxythymidine as Potential Anti-HIV Microbicides

by Hitesh K. Agarwal, Bhupender S. Chhikara, Guofeng Ye, Sitaram Bhavaraju, Ajay Dixit, Anil Kumar, Gustavo F. Doncel and Keykavous Parang

Molecules 2022, 27(10), 3352; https://doi.org/10.3390/molecules27103352 - 23 May 2022

Cited by 1 | Viewed by 3271

Abstract

A number of 5′-O-fatty acyl derivatives of 3′-fluoro-2′,3′-dideoxythymidine (FLT, 1) were synthesized. These conjugates were evaluated for their potential as topical microbicides with anti-HIV activity against cell-free (X4 and R5), cell-associated, and multidrug-resistant viruses. Compared to FLT and 3′-azido-2′,3′-dideoxythymidine (AZT), [...] Read more.

A number of 5′-O-fatty acyl derivatives of 3′-fluoro-2′,3′-dideoxythymidine (FLT, 1) were synthesized. These conjugates were evaluated for their potential as topical microbicides with anti-HIV activity against cell-free (X4 and R5), cell-associated, and multidrug-resistant viruses. Compared to FLT and 3′-azido-2′,3′-dideoxythymidine (AZT), 5′-O-(12-azidododecanoyl) (5), 5′-O-myristoyl (6), and 5′-O-(12-thioethyldodecanoyl) (8) derivatives of FLT were found to be more active against both cell-free viruses (lymphocytotropic and monocytotropic strains) with EC₅₀ values of 0.4 μM, 1.1 μM, and <0.2 μM, respectively, as well as cell-associated virus with EC₅₀ values of 12.6, 6.4, and 2.3 μM, respectively. Conjugates 5, 6, and 8 exhibited >4 and >30 times better antiviral index than FLT and AZT, respectively. Conjugates 5 and 8 were significantly more potent than FLT against many multidrug-resistant strains. A comparison of the anti-HIV activity with the corresponding non-hydrolyzable ether conjugates suggested that ester hydrolysis to FLT and fatty acids is critical to enable anti-HIV activity. Cellular uptake studies were conducted using fluorescent derivatives of FLT attached with 5(6)-carboxyfluorescein through either β-alanine (23) or 12-aminododecanoic acid (24) spacers. The lipophilic fluorescent analog with a long chain (24) showed more than 12 times higher cellular uptake profile than the fluorescent analog with a short chain (23). These studies further confirmed that the attachment of fatty acids improved the cellular uptake of nucleoside conjugates. In addition, 5, 6, and 8 were the least cytotoxic and did not alter vaginal cell and sperm viability compared to the positive control, a commercial topical spermicide (N-9), which significantly decreased sperm and vaginal cell viability inducing the generation of proinflammatory cytokines. Full article

(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)

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18 pages, 1340 KiB

Open AccessArticle

The Selection of the Optimal Impregnation Conditions of Vegetable Matrices with Iodine

by Agata Zaremba, Katarzyna Waszkowiak, Dominik Kmiecik, Anna Jędrusek-Golińska, Maciej Jarzębski and Krystyna Szymandera-Buszka

Molecules 2022, 27(10), 3351; https://doi.org/10.3390/molecules27103351 - 23 May 2022

Cited by 9 | Viewed by 2122

Abstract

This study aimed to determine the use of selected vegetables (pumpkin, cauliflower, broccoli, carrot) as carriers of potassium iodide (KI) and potassium iodate (KIO₃) by determining changes in iodine content under various conditions of impregnation as the degree of hydration, impregnated [...] Read more.

This study aimed to determine the use of selected vegetables (pumpkin, cauliflower, broccoli, carrot) as carriers of potassium iodide (KI) and potassium iodate (KIO₃) by determining changes in iodine content under various conditions of impregnation as the degree of hydration, impregnated sample temperature, and impregnation time. The influence of these conditions on iodine contents in vegetables after their fortification and storage (21 °C/230 days) was analyzed. The results showed that all selected vegetables could be efficient iodine carriers. However, the conditions of the impregnation process are crucial for fortification efficiency, particularly the degree of hydration and the temperature of the impregnated samples before drying. The results showed that the lowest iodine content was in samples fortified at 4 °C and 1:4 hydration. On the other hand, the highest reproducibility of iodine was for the following fortification conditions: temperature of −76 °C and hydration of 1:1. The studies confirmed the higher stability of iodine in KIO₃ form compared to KI. To increase recovery of the introduced iodine in the product after drying, using the conditioning step at 4 °C is not recommended. We recommend freezing vegetables immediately after the impregnation process Full article

(This article belongs to the Special Issue Advances in Critical Molecules Involved in the Pathophysiology of Thyroid Disease)

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19 pages, 3514 KiB

Open AccessFeature PaperArticle

Diclofenac Ion Hydration: Experimental and Theoretical Search for Anion Pairs

by Anastasia V. Shishkina, Alexander A. Ksenofontov, Nikita V. Penkov and Mikhail V. Vener

Molecules 2022, 27(10), 3350; https://doi.org/10.3390/molecules27103350 - 23 May 2022

Cited by 8 | Viewed by 3177

Abstract

Self-assembly of organic ions in aqueous solutions is a hot topic at the present time, and substances that are well-soluble in water are usually studied. In this work, aqueous solutions of sodium diclofenac are investigated, which, like most medicinal compounds, is poorly soluble [...] Read more.

Self-assembly of organic ions in aqueous solutions is a hot topic at the present time, and substances that are well-soluble in water are usually studied. In this work, aqueous solutions of sodium diclofenac are investigated, which, like most medicinal compounds, is poorly soluble in water. Classical MD modeling of an aqueous solution of diclofenac sodium showed equilibrium between the hydrated anion and the hydrated dimer of the diclofenac anion. The assignment and interpretation of the bands in the UV, NIR, and IR spectra are based on DFT calculations in the discrete-continuum approximation. It has been shown that the combined use of spectroscopic methods in various frequency ranges with classical MD simulations and DFT calculations provides valuable information on the association processes of medical compounds in aqueous solutions. Additionally, such a combined application of experimental and calculation methods allowed us to put forward a hypothesis about the mechanism of the effect of diclofenac sodium in high dilutions on a solution of diclofenac sodium. Full article

(This article belongs to the Special Issue Advances in Computational Spectroscopy)

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16 pages, 2118 KiB

Open AccessArticle

Degradation of Benzotriazole UV Stabilizers in PAA/d-Electron Metal Ions Systems—Removal Kinetics, Products and Mechanism Evaluation

by Dariusz Kiejza, Joanna Karpińska and Urszula Kotowska

Molecules 2022, 27(10), 3349; https://doi.org/10.3390/molecules27103349 - 23 May 2022

Cited by 17 | Viewed by 3333

Abstract

Benzotriazole UV stabilizers (BUVs) have gained popularity, due to their absorption properties in the near UV range (200–400 nm). They are used in the technology for manufacturing plastics, protective coatings, and cosmetics, to protect against the destructive influence of UV radiation. These compounds [...] Read more.

Benzotriazole UV stabilizers (BUVs) have gained popularity, due to their absorption properties in the near UV range (200–400 nm). They are used in the technology for manufacturing plastics, protective coatings, and cosmetics, to protect against the destructive influence of UV radiation. These compounds are highly resistant to biological and chemical degradation. As a result of insufficient treatment by sewage treatment plants, they accumulate in the environment and in the tissues of living organisms. BUVs have adverse effects on living organisms. This work presents the use of peracetic acid in combination with d-electron metal ions (Fe²⁺, Co²⁺), for the chemical oxidation of five UV filters from the benzotriazole group: 2-(2-hydroxy-5-methylphenyl)benzotriazole (UV-P), 2-tert-butyl-6-(5-chloro-2H-benzotriazol-2-yl)-4-methylphenol (UV-326), 2,4-di-tert-butyl-6-(5-chloro-2H-benzotriazol-2-yl)phenol (UV-327), 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV-328), and 2-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol (UV-329). The oxidation procedure has been optimized based on the design of experiments (DoE) methodology. The oxidation of benzotriazoles follows first order kinetics. The oxidation products of each benzotriazole were investigated, and the oxidation mechanisms of the tested compounds were proposed. Full article

(This article belongs to the Topic Catalytic Applications of Transition Metals)

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15 pages, 5686 KiB

Open AccessArticle

The Critical Role of 12-Methyl Group of Anthracycline Dutomycin to Its Antiproliferative Activity

by Ruoxuan Xu, Dinghang Hu, Jinlian Lin, Jie Tang, Ruoting Zhan, Guiyou Liu and Lei Sun

Molecules 2022, 27(10), 3348; https://doi.org/10.3390/molecules27103348 - 23 May 2022

Viewed by 2004

Abstract

Anthracycline dutomycin is a tetracyclic quinone glycoside produced by Streptomyces minoensis NRRL B-5482. SW91 is a C-12 demethylated dutomycin derivative, which was identified in our previous research. In vitro cytotoxicity and apoptosis assays of these two compounds were conducted to demonstrate their antiproliferation [...] Read more.

Anthracycline dutomycin is a tetracyclic quinone glycoside produced by Streptomyces minoensis NRRL B-5482. SW91 is a C-12 demethylated dutomycin derivative, which was identified in our previous research. In vitro cytotoxicity and apoptosis assays of these two compounds were conducted to demonstrate their antiproliferation activities. The results showed that both dutomycin and SW91 block cells at the S phase, whereas dutomycin shows more significant inhibition of cell growth. Their interactions with calf thymus DNA (CT-DNA) were investigated, with dutomycin exhibiting higher binding affinity. The molecular docking demonstrated that the 12-methyl group makes dutomycin attach to the groove of DNA. These findings suggest that dutomycin has binding higher affinity to DNA and impairs DNA replication resulting in more significant antitumor activity. Full article

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17 pages, 2735 KiB

Open AccessArticle

Fabrication and Evaluation of Voriconazole Loaded Transethosomal Gel for Enhanced Antifungal and Antileishmanial Activity

by Mudassir Farooq, Faisal Usman, Sumera Zaib, Hamid Saeed Shah, Qazi Adnan Jamil, Fatima Akbar Sheikh, Ajmal Khan, Sameh Rabea, Soheir A. A. Hagras, Gaber El-Saber Batiha and Imtiaz Khan

Molecules 2022, 27(10), 3347; https://doi.org/10.3390/molecules27103347 - 23 May 2022

Cited by 20 | Viewed by 4063

Abstract

Voriconazole (VRC) is a broad-spectrum antifungal agent belonging to BCS class II (biopharmaceutical classification system). Despite many efforts to enhance its solubility, this primary issue still remains challenging for formulation scientists. Transethosomes (TELs) are one of the potential innovative nano-carriers for improving the [...] Read more.

Voriconazole (VRC) is a broad-spectrum antifungal agent belonging to BCS class II (biopharmaceutical classification system). Despite many efforts to enhance its solubility, this primary issue still remains challenging for formulation scientists. Transethosomes (TELs) are one of the potential innovative nano-carriers for improving the solubility and permeation of poorly soluble and permeable drugs. We herein report voriconazole-loaded transethosomes (VRCT) fabricated by the cold method and followed by their incorporation into carbopol 940 as a gel. The prepared VRCT were evaluated for % yield, % entrapment efficiency (EE), surface morphology, possible chemical interaction, particle size, zeta potential, and polydispersity index (PDI). The optimized formulation had a particle size of 228.2 nm, a zeta potential of −26.5 mV, and a PDI of 0.45 with enhanced % EE. Rheology, spreadability, extrudability, in vitro release, skin permeation, molecular docking, antifungal, and antileishmanial activity were also assessed for VRCT and VRC loaded transethosomal gel (VTEG). Ex-vivo permeation using rat skin depicted a transdermal flux of 22.8 µg/cm²/h with enhanced efficiency up to 4-fold. A two-fold reduction in inhibitory as well as fungicidal concentration was observed against various fungal strains by VRCT and VTEG besides similar results against L-donovani. The development of transethosomal formulation can serve as an efficient drug delivery system through a topical route with enhanced efficacy and better patient compliance. Full article

(This article belongs to the Special Issue Recent Advances in Nano-Based Drug Delivery System)

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15 pages, 2572 KiB

Open AccessArticle

Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells

by Su Bin Kim, Yoon Sin Oh, Kwang Joon Kim, Sung Woo Cho, Seung Ki Park, Dong Jae Baek and Eun-Young Park

Molecules 2022, 27(10), 3346; https://doi.org/10.3390/molecules27103346 - 23 May 2022

Cited by 6 | Viewed by 2203

Abstract

Sphingosine kinase (SK) is involved in the growth of cells, including cancer cells. However, which of its two isotypes—SK1 and SK2—is more favorable for cancer growth remains unclear. Although PF-543 strongly and selectively inhibits SK1, its anticancer effect is not high, and the [...] Read more.

Sphingosine kinase (SK) is involved in the growth of cells, including cancer cells. However, which of its two isotypes—SK1 and SK2—is more favorable for cancer growth remains unclear. Although PF-543 strongly and selectively inhibits SK1, its anticancer effect is not high, and the underlying reason remains difficult to explain. We previously determined that the tail group of PF-543 is responsible for its low metabolic stability (MS). In this study, compounds containing aromatic or aliphatic tails in the triazole group were synthesized, and changes in the SK-inhibitory effect and anticancer activity of PF-543 were assessed using pancreatic cancer cells. The compounds with aliphatic tails showed high inhibitory effects on pancreatic cancer cells but slightly lower selectivity for SK1. A compound with an introduced aliphatic tail activated protein phosphatase 2A (PP2A), showing an effect similar to that of FTY720. Molecular docking analysis revealed that the PP2A-binding form of this newly synthesized compound was different from that noted in the case of FTY720. This compound also improved the MS of PF-543. These results indicate that the tail structure of PF-543 influences MS. Full article

(This article belongs to the Special Issue Medicinal Chemistry in Asia)

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12 pages, 2449 KiB

Open AccessArticle

1,2σ³λ³-Oxaphosphetanes and Their P-Chalcogenides—A Combined Experimental and Theoretical Study

by Florian Gleim, Antonio García Alcaraz, Gregor Schnakenburg, Arturo Espinosa Ferao and Rainer Streubel

Molecules 2022, 27(10), 3345; https://doi.org/10.3390/molecules27103345 - 23 May 2022

Cited by 1 | Viewed by 1746

Abstract

Although 1,2σ⁵λ⁵-oxaphosphetanes have been known for a long time, the “low-coordinate” 1,2σ³λ³-oxaphosphetanes have only been known since their first synthesis in 2018 via decomplexation. Apart from ligation of this P-heterocycle to gold(I)chloride and the oxidation [...] Read more.

Although 1,2σ⁵λ⁵-oxaphosphetanes have been known for a long time, the “low-coordinate” 1,2σ³λ³-oxaphosphetanes have only been known since their first synthesis in 2018 via decomplexation. Apart from ligation of this P-heterocycle to gold(I)chloride and the oxidation using ortho-chloranil, nothing on their chemistry has been reported so far. Herein, we describe the synthesis of new 1,2σ³λ³-oxaphosphetane complexes (3a–e) and free derivatives (4a–e), as well as reactions of 4a with chalcogens and/or chalcogen transfer reagents, which yielded the P-chalcogenides (14–16a; Ch = O, S, Se). We also report on the theoretical results of the reaction pathways of C-phenyl-substituted 1,2 σ³λ³-oxaphosphetanes and ring strain energies of 1,2σ⁴λ⁵-oxaphosphetane P-chalcogenides. Full article

(This article belongs to the Special Issue Organophosphorus Chemistry: A Themed Issue in Honor of Prof. Koop Lammertsma)

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8 pages, 566 KiB

Open AccessArticle

Four New Sesquiterpenoids from the Rice Fermentation of Antrodiella albocinnamomea

by Min Guo, Ying-Zhong Liang, Xiu-Ming Cui, Lin-Jiao Shao, Yin-Fei Li and Xiao-Yan Yang

Molecules 2022, 27(10), 3344; https://doi.org/10.3390/molecules27103344 - 23 May 2022

Viewed by 1828

Abstract

Albocimea B-E (1–4), four new sesquiterpenoids, and four known compounds, steperoxide A (5), dankasterone (6), 1H-indole-3-carboxylic acid (7), and (+)-formylanserinone B (8), were isolated from the rice fermentation of [...] Read more.

Albocimea B-E (1–4), four new sesquiterpenoids, and four known compounds, steperoxide A (5), dankasterone (6), 1H-indole-3-carboxylic acid (7), and (+)-formylanserinone B (8), were isolated from the rice fermentation of the fungus Antrodiella albocinnamomea. The structures of new compounds were elucidated by comprehensive spectroscopic techniques, the planar structures of new compounds were determined by comprehensive spectroscopic techniques, and their absolute configurations were confirmed via gauge-independent atomic orbital calculations (GIAO), calculation of the electronic circular dichroism (ECD), and optical rotation (OR). These were determined by spectroscopic data analysis. Full article

(This article belongs to the Special Issue Isolation, Identification and Application of Biologically Active Natural Products)

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14 pages, 6631 KiB

Open AccessArticle

Impact of Electrospinning Parameters and Post-Treatment Method on Antibacterial and Antibiofilm Activity of Chitosan Nanofibers

by Viktoriia Korniienko, Yevheniia Husak, Julia Radwan-Pragłowska, Viktoriia Holubnycha, Yevhen Samokhin, Anna Yanovska, Julia Varava, Kateryna Diedkova, Łukasz Janus and Maksym Pogorielov

Molecules 2022, 27(10), 3343; https://doi.org/10.3390/molecules27103343 - 23 May 2022

Cited by 12 | Viewed by 2925

Abstract

Chitosan, a natural biopolymer, is an ideal candidate to prepare biomaterials capable of preventing microbial infections due to its antibacterial properties. Electrospinning is a versatile method ideally suited to process biopolymers with minimal impact on their physicochemical properties. However, fabrication parameters and post-processing [...] Read more.

Chitosan, a natural biopolymer, is an ideal candidate to prepare biomaterials capable of preventing microbial infections due to its antibacterial properties. Electrospinning is a versatile method ideally suited to process biopolymers with minimal impact on their physicochemical properties. However, fabrication parameters and post-processing routine can affect biological activity and, therefore, must be well adjusted. In this study, nanofibrous membranes were prepared using trifluoroacetic acid and dichloromethane and evaluated for physiochemical and antimicrobial properties. The use of such biomaterials as potential antibacterial agents was extensively studied in vitro using Staphylococcus aureus and Escherichia coli as test organisms. The antibacterial assay showed inhibition of bacterial growth and eradication of the planktonic cells of both E. coli and S. aureus in the liquid medium for up to 6 hrs. The quantitative assay showed a significant reduction in bacteria cell viability by nanofibers depending on the method of fabrication. The antibacterial properties of these biomaterials can be attributed to the structural modifications provided by co-solvent formulation and application of post-treatment procedure. Consequently, the proposed antimicrobial surface modification method is a promising technique to prepare biomaterials designed to induce antimicrobial resistance via antiadhesive capability and the biocide-releasing mechanism. Full article

(This article belongs to the Special Issue Natural Products with Biological and Therapeutic Activity)

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11 pages, 1508 KiB

Open AccessArticle

Iminosugar Amino Acid idoBR1 Reduces Inflammatory Responses in Microglia

by Olumayokun A. Olajide, Victoria U. Iwuanyanwu, Owolabi W. Banjo, Atsushi Kato, Yana B. Penkova, George W. J. Fleet and Robert J. Nash

Molecules 2022, 27(10), 3342; https://doi.org/10.3390/molecules27103342 - 23 May 2022

Cited by 2 | Viewed by 3048

Abstract

(1) Background. Inflammation is reported to be a key factor in neurodegeneration. The microglia are immune cells present in the central nervous system; their activation results in the release of inflammatory cytokines and is thought to be related to aging and neurodegenerative disorders, [...] Read more.

(1) Background. Inflammation is reported to be a key factor in neurodegeneration. The microglia are immune cells present in the central nervous system; their activation results in the release of inflammatory cytokines and is thought to be related to aging and neurodegenerative disorders, such as Alzheimer’s disease. (2) Methods. A mouse BV-2 microglia cell line was activated using LPS and the anti-inflammatory cucumber-derived iminosugar amino acid idoBR1, (2R,3R,4R,5S)-3,4,5-trihydroxypiperidine-2-carboxylic acid, was used alongside dexamethasone as the control to determine whether it could reduce the inflammatory responses. (3) Results. A dose-dependent reduction in the LPS-induced production of the proinflammatory factors TNFα, IL-6, and nitric oxide and the transcription factor NF-κB was found. (4) Conclusions. Further investigations of the anti-inflammatory effects of idoBR1 in other models of neurodegenerative diseases are warranted. Full article

(This article belongs to the Special Issue Iminosugars: Beyond Glycosidase Inhibition)

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12 pages, 2834 KiB

Open AccessArticle

Functional Characterization of Flavanone 3-Hydroxylase (F3H) and Its Role in Anthocyanin and Flavonoid Biosynthesis in Mulberry

by Mingjie Dai, Xiaoru Kang, Yuqiong Wang, Shuai Huang, Yangyang Guo, Rufeng Wang, Nan Chao and Li Liu

Molecules 2022, 27(10), 3341; https://doi.org/10.3390/molecules27103341 - 23 May 2022

Cited by 36 | Viewed by 3483

Abstract

Mulberry (Morus spp., Moraceae) is an important economic crop plant and is rich in flavonoids and anthocyanidins in ripe fruits. Anthocyanins are glycosides of anthocyanidins. Flavanone 3-hydroxylase (F3H) catalyzes the conversion of naringenin into dihydroflavonols and is responsible for the biosynthesis of [...] Read more.

Mulberry (Morus spp., Moraceae) is an important economic crop plant and is rich in flavonoids and anthocyanidins in ripe fruits. Anthocyanins are glycosides of anthocyanidins. Flavanone 3-hydroxylase (F3H) catalyzes the conversion of naringenin into dihydroflavonols and is responsible for the biosynthesis of flavonols and anthocyanidins. In this study, MazsF3H was cloned and characterized from Morus atropurpurea var. Zhongshen 1. Conserved motif analysis based on alignment and phylogenetic analysis indicated that MazsF3H belonged to 2-oxoglutarate-dependent dioxygenase and MazsF3H clustered with F3Hs from other plants. MazsF3H was located in both nucleus and cytosol. MazsF3H was expressed in stems, leaves, stigmas and ovaries, except buds. F3H expression levels showed a positive and close relationship with anthocyanin content during the anthocyanin-rich fruit ripening process, while it showed a negative correlation with anthocyanin content in LvShenZi, whose fruits are white and would not experience anthocyanin accumulation during fruit ripening. Significantly different F3H expression levels were also found in different mulberry varieties that have quite different anthocyanin contents in ripe fruits. Overexpression MazsF3H in tobacco showed unexpected results, including decreased anthocyanin content. Down-regulation of F3H expression levels resulted in co-expression of the genes involved in anthocyanin biosynthesis and a significant decrease in anthocyanin content, but the change in total flavonoid content was subtle. Our results indicated that F3H may play quite different roles in different varieties that have quite different fruit colors. In addition, possible complex regulation of flavonoid biosynthesis should be further explored in some of the featured plant species. Full article

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11 pages, 2157 KiB

Open AccessArticle

Computer-Aided Detection of Quantitative Signatures for Breast Fibroepithelial Tumors Using Label-Free Multi-Photon Imaging

by Kana Kobayashi-Taguchi, Takashi Saitou, Yoshiaki Kamei, Akari Murakami, Kanako Nishiyama, Reina Aoki, Erina Kusakabe, Haruna Noda, Michiko Yamashita, Riko Kitazawa, Takeshi Imamura and Yasutsugu Takada

Molecules 2022, 27(10), 3340; https://doi.org/10.3390/molecules27103340 - 23 May 2022

Cited by 2 | Viewed by 2826

Abstract

Fibroadenomas (FAs) and phyllodes tumors (PTs) are major benign breast tumors, pathologically classified as fibroepithelial tumors. Although the clinical management of PTs differs from FAs, distinction by core needle biopsy diagnoses is still challenging. Here, a combined technique of label-free imaging with multi-photon [...] Read more.

Fibroadenomas (FAs) and phyllodes tumors (PTs) are major benign breast tumors, pathologically classified as fibroepithelial tumors. Although the clinical management of PTs differs from FAs, distinction by core needle biopsy diagnoses is still challenging. Here, a combined technique of label-free imaging with multi-photon microscopy and artificial intelligence was applied to detect quantitative signatures that differentiate fibroepithelial lesions. Multi-photon excited autofluorescence and second harmonic generation (SHG) signals were detected in tissue sections. A pixel-wise semantic segmentation method using a deep learning framework was used to separate epithelial and stromal regions automatically. The epithelial to stromal area ratio and the collagen SHG signal strength were investigated for their ability to distinguish fibroepithelial lesions. An image segmentation analysis with a pixel-wise semantic segmentation framework using a deep convolutional neural network showed the accurate separation of epithelial and stromal regions. A further investigation, to determine if scoring the epithelial to stromal area ratio and the SHG signal strength within the stromal area could be a marker for differentiating fibroepithelial tumors, showed accurate classification. Therefore, molecular and morphological changes, detected through the assistance of computational and label-free multi-photon imaging techniques, enable us to propose quantitative signatures for epithelial and stromal alterations in breast tissues. Full article

(This article belongs to the Special Issue Autofluorescence Spectroscopy and Imaging II)

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20 pages, 2654 KiB

Open AccessArticle

Safety Assessment and Pain Relief Properties of Saffron from Taliouine Region (Morocco)

by Maroua Ait Tastift, Rachida Makbal, Thouria Bourhim, Zineb Omari, Hiroko Isoda and Chemseddoha Gadhi

Molecules 2022, 27(10), 3339; https://doi.org/10.3390/molecules27103339 - 23 May 2022

Cited by 4 | Viewed by 3636

Abstract

Saffron is the most expensive spice in the world. In addition to its culinary utilization, this spice is used for medicinal purposes such as in pain management. In this study, the analgesic activity of Crocus sativus stigma extract (CSSE) was evaluated in rodents [...] Read more.

Saffron is the most expensive spice in the world. In addition to its culinary utilization, this spice is used for medicinal purposes such as in pain management. In this study, the analgesic activity of Crocus sativus stigma extract (CSSE) was evaluated in rodents and its possible physiological mechanism was elucidated. The anti-nociceptive effect of CSSE was evaluated using three animal models (hot plate, writhing, and formalin tests). The analgesic pathways involved were assessed using various analgesia-mediating receptors antagonists. The oral administration of CSSE, up to 2000 mg/kg, caused no death or changes in the behavior or in the hematological and biochemical blood parameters of treated animals nor in the histological architecture of the animals’ livers and kidneys. CSSE showed a central, dose-dependent, anti-nociceptive effect in response to thermal stimuli; and a peripheral analgesic effect in the test of contortions induced by acetic acid. The dual (central and peripheral) analgesic effect was confirmed by the formalin test. The anti-nociceptive activity of CSSE was totally or partially reversed by the co-administration of receptor antagonists, naloxone, atropine, haloperidol, yohimbine, and glibenclamide. CSSE influenced signal processing, by the modulation of the opioidergic, adrenergic, and muscarinic systems at the peripheral and central levels; and by regulation of the dopaminergic system and control of the opening of the ATP-sensitive K⁺ channels at the spinal level. The obtained data point to a multimodal mechanism of action for CSSE: An anti-inflammatory effect and a modulation, through different physiological pathways, of the electrical signal generated by the nociceptors. Further clinical trials are required to endorse the potential utilization of Moroccan saffron as a natural painkiller. Full article

(This article belongs to the Special Issue The Functional Applications of Medicinal Plants)

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26 pages, 4078 KiB

Open AccessArticle

New Cu⁺² Complexes with N-Sulfonamide Ligands: Potential Antitumor, Antibacterial, and Antioxidant Agents

by Adriana Corina Hangan, Alexandru Turza, Roxana Liana Lucaciu, Bogdan Sevastre, Emőke Páll, Luminița Simona Oprean and Gheorghe Borodi

Molecules 2022, 27(10), 3338; https://doi.org/10.3390/molecules27103338 - 23 May 2022

Cited by 8 | Viewed by 2836

Abstract

Nowadays, the discovery of a new non-toxic metal complex with biological activity represents a very active area of research. Two Cu⁺² complexes, [Cu(L1)₂(H₂O)₃] (C1) (HL1= N-(5-(4-methylphenyl)-[1,3,4]–thiadiazole–2-yl)-naphtalenesulfonamide) and [Cu(L2)₂(py)₂(H₂O)] (C2) (HL2= [...] Read more.

Nowadays, the discovery of a new non-toxic metal complex with biological activity represents a very active area of research. Two Cu⁺² complexes, [Cu(L1)₂(H₂O)₃] (C1) (HL1= N-(5-(4-methylphenyl)-[1,3,4]–thiadiazole–2-yl)-naphtalenesulfonamide) and [Cu(L2)₂(py)₂(H₂O)] (C2) (HL2= N-(5-ethyl-[1,3,4]–thiadiazole–2-yl)-naphtalenesulfonamide), with two new ligands were synthesized. The X-ray crystal structures of the complexes were determined. In both complexes, Cu⁺² is five-coordinated, forming a CuN₂O₃ and CuN₄O chromophore, respectively. The ligands act as monodentate, coordinating the metal ion through a single N_thiadiazole atom; for the C2 complex, the molecules from the reaction medium (pyridine and water) are also involved in the coordination of Cu⁺². The complexes have a distorted square pyramidal square-planar geometry. The compounds were characterized by FT-IR, electronic EPR spectroscopy, and magnetic methods. The nuclease activity studies confirm the complexes’ capacity to cleave the DNA molecule. Using a xanthine-xanthine oxydase system, the SOD mimetic activity of the complexes was demonstrated. Cytotoxicity studies were carried out on two tumor cell lines (HeLa, WM35) and on a normal cell line (HFL1) using the MTT method, with cisplatin used as a positive control. The antibacterial activity of the complexes was investigated against two Gram-positive and two Gram-negative bacteria, and compared with Amoxicillin and Norfloxacin using the disk diffusion method. Both complexes showed in vitro biological activity but the C2 complex was more active. A lack of in vivo toxicity was demonstrated for the C2 complex by performing hepatic, renal, and hematological studies on Swiss mice. Full article

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18 pages, 3720 KiB

Open AccessArticle

Influence of 40 Hz and 100 Hz Vibration on SH-SY5Y Cells Growth and Differentiation—A Preliminary Study

by Patrycja Grosman-Dziewiszek, Benita Wiatrak, Wojciech Dziewiszek, Paulina Jawień, Remigiusz Mydlikowski, Romuald Bolejko, Marta Szandruk-Bender, Ewa Karuga-Kuźniewska and Adam Szeląg

Molecules 2022, 27(10), 3337; https://doi.org/10.3390/molecules27103337 - 23 May 2022

Cited by 1 | Viewed by 5101

Abstract

(1) Background: A novel bioreactor platform of neuronal cell cultures using low-magnitude, low-frequency (LMLF) vibrational stimulation was designed to discover vibration influence and mimic the dynamic environment of the in vivo state. To better understand the impact of 40 Hz and 100 Hz [...] Read more.

(1) Background: A novel bioreactor platform of neuronal cell cultures using low-magnitude, low-frequency (LMLF) vibrational stimulation was designed to discover vibration influence and mimic the dynamic environment of the in vivo state. To better understand the impact of 40 Hz and 100 Hz vibration on cell differentiation, we join biotechnology and advanced medical technology to design the nano-vibration system. The influence of vibration on the development of nervous tissue on the selected cell line SH-SY5Y (experimental research model in Alzheimer’s and Parkinson’s) was investigated. (2) Methods: The vibration stimulation of cell differentiation and elongation of their neuritis were monitored. We measured how vibrations affect the morphology and differentiation of nerve cells in vitro. (3) Results: The highest average length of neurites was observed in response to the 40 Hz vibration on the collagen surface in the differentiating medium, but cells response did not increase with vibration frequency. Also, vibrations at a frequency of 40 Hz or 100 Hz did not affect the average density of neurites. 100 Hz vibration increased the neurites density significantly with time for cultures on collagen and non-collagen surfaces. The exposure of neuronal cells to 40 Hz and 100 Hz vibration enhanced cell differentiation. The 40 Hz vibration has the best impact on neuronal-like cell growth and differentiation. (4) Conclusions: The data demonstrated that exposure to neuronal cells to 40 Hz and 100 Hz vibration enhanced cell differentiation and proliferation. This positive impact of vibration can be used in tissue engineering and regenerative medicine. It is planned to optimize the processes and study its molecular mechanisms concerning carrying out the research. Full article

(This article belongs to the Special Issue Molecular Targets in Neuroscience and Neurotherapeutics)

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13 pages, 2911 KiB

Open AccessArticle

Cyanide Biodegradation by Trichoderma harzianum and Cyanide Hydratase Network Analysis

by Narges Malmir, Mohammadreza Zamani, Mostafa Motallebi, Najaf Allahyari Fard and Lukhanyo Mekuto

Molecules 2022, 27(10), 3336; https://doi.org/10.3390/molecules27103336 - 23 May 2022

Cited by 6 | Viewed by 2505

Abstract

Cyanide is a poisonous and dangerous chemical that binds to metals in metalloenzymes, especially cytochrome C oxidase and, thus, interferes with their functionalities. Different pathways and enzymes are involved during cyanide biodegradation, and cyanide hydratase is one of the enzymes that is involved [...] Read more.

Cyanide is a poisonous and dangerous chemical that binds to metals in metalloenzymes, especially cytochrome C oxidase and, thus, interferes with their functionalities. Different pathways and enzymes are involved during cyanide biodegradation, and cyanide hydratase is one of the enzymes that is involved in such a process. In this study, cyanide resistance and cyanide degradation were studied using 24 fungal strains in order to find the strain with the best capacity for cyanide bioremediation. To confirm the capacity of the tested strains, cyano-bioremediation and the presence of the gene that is responsible for the cyanide detoxification was assessed. From the tested organisms, Trichoderma harzianum (T. harzianum) had a significant capability to resist and degrade cyanide at a 15 mM concentration, where it achieved an efficiency of 75% in 7 days. The gene network analysis of enzymes that are involved in cyanide degradation revealed the involvement of cyanide hydratase, dipeptidase, carbon–nitrogen hydrolase-like protein, and ATP adenylyltransferase. This study revealed that T. harzianum was more efficient in degrading cyanide than the other tested fungal organisms, and molecular analysis confirmed the experimental observations. Full article

(This article belongs to the Special Issue Molecules in 2022)

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23 pages, 6630 KiB

Open AccessArticle

Design, Synthesis, Bioactivity Evaluation, Crystal Structures, and In Silico Studies of New α-Amino Amide Derivatives as Potential Histone Deacetylase 6 Inhibitors

by Yangrong Xu, Hangjun Tang, Yijie Xu, Jialin Guo, Xu Zhao, Qingguo Meng and Junhai Xiao

Molecules 2022, 27(10), 3335; https://doi.org/10.3390/molecules27103335 - 22 May 2022

Cited by 3 | Viewed by 2890

Abstract

Hydroxamate, as a zinc-binding group (ZBG), prevails in the design of histone deacetylase 6(HDAC6) inhibitors due to its remarkable zinc-chelating capability. However, hydroxamate-associated genotoxicity and mutagenicity have limited the widespread application of corresponding HDAC6 inhibitors in the treatment of human diseases. To avoid [...] Read more.

Hydroxamate, as a zinc-binding group (ZBG), prevails in the design of histone deacetylase 6(HDAC6) inhibitors due to its remarkable zinc-chelating capability. However, hydroxamate-associated genotoxicity and mutagenicity have limited the widespread application of corresponding HDAC6 inhibitors in the treatment of human diseases. To avoid such side effects, researchers are searching for novel ZBGs that may be used for the synthesis of HDAC6 inhibitors. In this study, a series of stereoisomeric compounds were designed and synthesized to discover non-hydroxamate HDAC6 inhibitors using α-amino amide as zinc-ion-chelating groups, along with a pair of enantiomeric isomers with inverted L-shaped vertical structure as cap structures. The anti-proliferative activities were determined against HL-60, Hela, and RPMI 8226 cells, and 7a and its stereoisomer 13a exhibited excellent activities against Hela cells with IC₅₀ = 0.31 µM and IC₅₀ = 5.19 µM, respectively. Interestingly, there is a significant difference between the two stereoisomers. Moreover, an evaluation of cytotoxicity toward human normal liver cells HL-7702 indicated its safety for normal cells. X-ray single crystal diffraction was employed to increase insights into molecule structure and activities. It was found that the carbonyl of the amide bond is on the different side from the amino and pyridine nitrogen atoms. To identify possible protein targets to clarify the mechanism of action and biological activity of 7a, a small-scale virtual screen using reverse docking for HDAC isoforms (1–10) was performed and the results showed that HDAC6 was the best receptor for 7a, suggesting that HDAC6 may be a potential target for 7a. The interaction pattern analysis showed that the α-amino amide moiety of 7a coordinated with the zinc ion of HDAC6 in a bidentate chelate manner, which is similar to the chelation pattern of hydroxamic acid. Finally, the molecular dynamics simulation approaches were used to assess the docked complex’s conformational stability. In this work, we identified 7a as a potential HDAC6 inhibitor and provide some references for the discovery of non-hydroxamic acid HDAC6 inhibitors. Full article

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13 pages, 992 KiB

Open AccessArticle

Polycyclic Phenol Derivatives from the Leaves of Spermacoce latifolia and Their Antibacterial and α-Glucosidase Inhibitory Activity

by Shao-Bo Liu, Lei Zeng, Qiao-Lin Xu, Ying-Le Chen, Tao Lou, Shan-Xuan Zhang and Jian-Wen Tan

Molecules 2022, 27(10), 3334; https://doi.org/10.3390/molecules27103334 - 22 May 2022

Cited by 6 | Viewed by 2494

Abstract

Three new polycyclic phenol derivatives, 2-acetyl-4-hydroxy-6H-furo [2,3-g]chromen-6-one (1), 2-(1′,2′-dihydroxypropan-2′-yl)-4-hydroxy-6H-furo [2,3-g][1]benzopyran-6-one (2) and 3,8,10-trihydroxy-4,9-dimethoxy-6H-benzo[c]chromen-6-one (8), along with seven known ones (3–7, 9 and 10) were isolated for the first time from the leaves [...] Read more.

Three new polycyclic phenol derivatives, 2-acetyl-4-hydroxy-6H-furo [2,3-g]chromen-6-one (1), 2-(1′,2′-dihydroxypropan-2′-yl)-4-hydroxy-6H-furo [2,3-g][1]benzopyran-6-one (2) and 3,8,10-trihydroxy-4,9-dimethoxy-6H-benzo[c]chromen-6-one (8), along with seven known ones (3–7, 9 and 10) were isolated for the first time from the leaves of Spermacoce latifolia. Their structures were determined by spectroscopic analysis and comparison with literature-reported data. These compounds were tested for their in vitro antibacterial activity against four Gram-(+) bacteria: Staphyloccocus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), Bacillus cereus (BC), Bacillus subtilis (BS), and the Gram-(−) bacterium Escherichia coli. Compounds 1, 2, 5 and 8 showed antibacterial activity toward SA, BC and BS with MIC values ranging from 7.8 to 62.5 µg/mL, but they were inactive to MRSA. Compound 4 not only showed the best antibacterial activity against SA, BC and BS, but it further displayed significant antibacterial activity against MRSA (MIC 1.95 µg/mL) even stronger than vancomycin (MIC 3.9 µg/mL). No compounds showed inhibitory activity toward E. coli. Further bioassay indicated that compounds 1, 4, 5, 6, 8 and 9 showed in vitro α-glucosidase inhibitory activity, among which compound 9 displayed the best α-glucosidase inhibitory activity with IC₅₀ value (0.026 mM) about 15-fold stronger than the reference compound acarbose (IC₅₀ 0.408 mM). These results suggested that compounds 4, 8 and 9 were potentially highly valuable compounds worthy of consideration to be further developed as an effective anti-MRSA agent or effective α-glucosidase inhibitors, respectively. In addition, the obtained data also supported that S. latifolia was rich in structurally diverse bioactive compounds worthy of further investigation, at least in searching for potential antibiotics and α-glucosidase inhibitors. Full article

(This article belongs to the Special Issue Bioactive Compounds from Natural Sources: Characterization and Biological Evaluation)

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14 pages, 3596 KiB

Open AccessArticle

Novel Oxime Synthesized from a Natural Product of Senecio nutans SCh. Bip. (Asteraceae) Enhances Vascular Relaxation in Rats by an Endothelium-Independent Mechanism

by Javier Palacios, Adrián Paredes, Marcelo A. Catalán, Chukwuemeka R. Nwokocha and Fredi Cifuentes

Molecules 2022, 27(10), 3333; https://doi.org/10.3390/molecules27103333 - 22 May 2022

Cited by 3 | Viewed by 2528

Abstract

Senecio nutans Sch. Bip. and its constituents are reported to have antihypertensive effects. We isolated metabolite–1, a natural compound from S. nutans (4-hydroxy-3-(isopenten-2-yl)-acetophenone), and synthesized novel oxime – 1 (4-hydroxy-3-(isopenten-2-yl)-acetophenoxime) to evaluate their effect on vascular reactivity. Compounds were purified (metabolite–1) or synthetized [...] Read more.

Senecio nutans Sch. Bip. and its constituents are reported to have antihypertensive effects. We isolated metabolite–1, a natural compound from S. nutans (4-hydroxy-3-(isopenten-2-yl)-acetophenone), and synthesized novel oxime – 1 (4-hydroxy-3-(isopenten-2-yl)-acetophenoxime) to evaluate their effect on vascular reactivity. Compounds were purified (metabolite–1) or synthetized (oxime–1) and characterized using IR and NMR spectroscopy and Heteronuclear Multiple Quantum Coherence (HMQC). Using pharmacological agents such as phenylephrine (PE) and KCl (enhancing contraction), acetylcholine (ACh), L-NAME (nitric oxide (NO) and endothelial function), Bay K8644-induced Ca_V1.2 channel (calcium channel modulator), and isolated aortic rings in an organ bath setup, the possible mechanisms of vascular action were determined. Pre-incubation of aortic rings with 10⁻⁵ M oxime–1 significantly (p < 0.001) decreased the contractile response to 30 mM KCl. EC₅₀ to KCl significantly (p < 0.01) increased in the presence of oxime–1 (37.72 ± 2.10 mM) compared to that obtained under control conditions (22.37 ± 1.40 mM). Oxime–1 significantly reduced (p < 0.001) the contractile response to different concentrations of PE (10⁻⁷ to 10⁻⁵ M) by a mechanism that decreases Cav1.2-mediated Ca²⁺ influx from the extracellular space and reduces Ca²⁺ release from intracellular stores. At a submaximal concentration (10⁻⁵ M), oxime–1 caused a significant relaxation in rat aorta even without vascular endothelium or after pre-incubate the tissue with L-NAME. Oxime–1 decreases the contractile response to PE by blunting the release of Ca²⁺ from intracellular stores and blocking of Ca²⁺ influx by channels. Metabolite–1 reduces the contractile response to KCl, apparently by reducing the plasma membrane depolarization and Ca²⁺ influx from the extracellular space. These acetophenone derivates from S. nutans (metabolite–1 and oxime–1) cause vasorelaxation through pathways involving an increase of the endothelial NO generation or a higher bioavailability, further highlighting that structural modification of naturally occurring metabolites can enhance their intended pharmacological functions. Full article

(This article belongs to the Section Natural Products Chemistry)

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15 pages, 3346 KiB

Open AccessArticle

Histone Deacetylase Inhibitory Activity and Antiproliferative Potential of New [6]-Shogaol Derivatives

by Chanokbhorn Phaosiri, Chavi Yenjai, Thanaset Senawong, Gulsiri Senawong, Somprasong Saenglee, La-or Somsakeesit and Pakit Kumboonma

Molecules 2022, 27(10), 3332; https://doi.org/10.3390/molecules27103332 - 22 May 2022

Cited by 6 | Viewed by 2869

Abstract

Twenty newly synthesized derivatives of [6]-shogaol (4) were tested for inhibitory activity against histone deacetylases. All derivatives showed moderate to good histone deacetylase inhibition at 100 µM with a slightly lower potency than the lead compound. Most potent inhibitors among the [...] Read more.

Twenty newly synthesized derivatives of [6]-shogaol (4) were tested for inhibitory activity against histone deacetylases. All derivatives showed moderate to good histone deacetylase inhibition at 100 µM with a slightly lower potency than the lead compound. Most potent inhibitors among the derivatives were the pyrazole products, 5j and 5k, and the Michael adduct with pyridine 4c and benzothiazole 4d, with IC₅₀ values of 51, 65, 61 and 60 µM, respectively. They were further evaluated for isoform selectivity via a molecular docking study. Compound 4d showed the best selectivity towards HDAC3, whereas compound 5k showed the best selectivity towards HDAC2. The potential derivatives were tested on five cancer cell lines, including human cervical cancer (HeLa), human colon cancer (HCT116), human breast adenocarcinoma cancer (MCF-7), and cholangiocarcinoma (KKU100 and KKU-M213B) cells with MTT-based assay. The most active histone deacetylase inhibitor 5j exhibited the best antiproliferative activity against HeLa, HCT116, and MCF-7, with IC₅₀ values of 8.09, 9.65 and 11.57 µM, respectively, and a selective binding to HDAC1 based on molecular docking experiments. The results suggest that these compounds can be putative candidates for the development of anticancer drugs via inhibiting HDACs. Full article

(This article belongs to the Special Issue Heterocyclic Building Blocks for Medicinal Applications)

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16 pages, 2824 KiB

Open AccessArticle

Chemical Modification of Biomarkers through Accelerated Degradation: Implications for Ancient Plant Identification in Archaeo-Organic Residues

by Barbara Huber, Daniel Giddings Vassão, Patrick Roberts, Yiming V. Wang and Thomas Larsen

Molecules 2022, 27(10), 3331; https://doi.org/10.3390/molecules27103331 - 22 May 2022

Cited by 3 | Viewed by 3645

Abstract

Biochemical and biomolecular archaeology is increasingly used to elucidate the consumption, use, origin, and trade of plants in the past. However, it can be challenging to use biomarkers to identify the taxonomic origin of archaeological plants due to limited knowledge of molecular survival [...] Read more.

Biochemical and biomolecular archaeology is increasingly used to elucidate the consumption, use, origin, and trade of plants in the past. However, it can be challenging to use biomarkers to identify the taxonomic origin of archaeological plants due to limited knowledge of molecular survival and degradation for many key plant compounds in archaeological contexts. To gain a fundamental understanding of the chemical alterations associated with chemical degradation processes in ancient samples, we conducted accelerated degradation experiments with essential oil derived from cedar (Cedrus atlantica) exposed to materials commonly found in the archaeological record. Using GC-MS and multivariate analysis, we detected a total of 102 compounds across 19 treatments that were classified into three groups. The first group comprised compounds that were abundant in fresh cedar oil but would be unlikely to remain in ancient residues due to rapid degradation. The second group consisted of compounds that remained relatively stable or increased over time, which could be potential biomarkers for identifying cedar in archaeological residues. Compounds in the third group were absent in fresh cedar oil but were formed during specific experiments that could be indicative for certain storage conditions. These results show that caution is warranted for applying biomolecular profiles of fresh plants to ancient samples and that carefully designed accelerated degradation experiments can, at least in part, overcome this limitation. Full article

(This article belongs to the Special Issue Chemistry and Archaeology: A Unique System to Inquire the Past)

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11 pages, 4163 KiB

Open AccessArticle

Thermo-Responsive ZnPc-g-TiO₂-g-PNIPAM Photocatalysts Sensitized with Phthalocyanines for Water Purification under Visible Light

by Bingxin Mao, Cong Liu, Xu Cui, Yanhui Li and Qian Duan

Molecules 2022, 27(10), 3330; https://doi.org/10.3390/molecules27103330 - 22 May 2022

Cited by 2 | Viewed by 1983

Abstract

A novel thermo-responsive 2,9(10),16(17),23(24)-tetrakis[(3-carboxyacrylamide) phthalocyaninato] zinc (ZnPc)-g-TiO₂-g-poly(N-isopropylacrylamide) (PNIPAM) photocatalyst modified with phthalocyanines was prepared. The photocatalyst exhibited thermo-responsive properties due to the introduction of PNIPAM, which performed recovery for reuse above the lower critical solution [...] Read more.

A novel thermo-responsive 2,9(10),16(17),23(24)-tetrakis[(3-carboxyacrylamide) phthalocyaninato] zinc (ZnPc)-g-TiO₂-g-poly(N-isopropylacrylamide) (PNIPAM) photocatalyst modified with phthalocyanines was prepared. The photocatalyst exhibited thermo-responsive properties due to the introduction of PNIPAM, which performed recovery for reuse above the lower critical solution temperature (LCST, about 26 °C). ZnPc-g-TiO₂-g-PNIPAM effectively expanded the light response range to the visible light region and inhibited the recombination of electron–hole pairs, which enhanced the performance of the photocatalyst. As expected, ZnPc-g-TiO₂-g-PNIPAM (0.3 g/L) exhibited excellent photocatalytic performance for the removal of Rhodamine B (RhB, 1.0 × 10⁻⁵ mol/L) and methylene blue (MB, 1.0 × 10⁻⁵ mol/L) under visible light, which reached 97.2% and 88.6% at 20 °C within 40 min, respectively. Furthermore, the influence of temperature upon photocatalytic performance was also investigated. When the temperature increased from 20 °C to 45 °C, the removal of RhB decreased by approximately 53.8%. The stability of the photocatalyst demonstrated that the photocatalytic activity was still above 80% for the removal of RhB after 3 cycles. Above all, this work provided an intelligent thermally responsive photocatalyst based on phthalocyanine for water purification under visible light. Full article

(This article belongs to the Section Photochemistry)

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Molecules, Volume 27, Issue 10 (May-2 2022) – 315 articles

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