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23 pages, 6746 KiB

Open AccessArticle

Biological Activities and ADMET-Related Properties of Novel Set of Cinnamanilides

by Jiri Kos, Andrzej Bak, Violetta Kozik, Timotej Jankech, Tomas Strharsky, Aleksandra Swietlicka, Hana Michnova, Jan Hosek, Adam Smolinski, Michal Oravec, Ferdinand Devinsky, Milan Hutta and Josef Jampilek

Molecules 2020, 25(18), 4121; https://doi.org/10.3390/molecules25184121 - 9 Sep 2020

Cited by 9 | Viewed by 2612

Abstract

A series of nineteen novel ring-substituted N-arylcinnamanilides was synthesized and characterized. All investigated compounds were tested against Staphylococcus aureus as the reference strain, two clinical isolates of methicillin-resistant S. aureus (MRSA), and Mycobacterium tuberculosis. (2E)-N-[3-Fluoro-4-(trifluoromethyl)phenyl]-3-phenylprop-2-enamide showed even [...] Read more.

A series of nineteen novel ring-substituted N-arylcinnamanilides was synthesized and characterized. All investigated compounds were tested against Staphylococcus aureus as the reference strain, two clinical isolates of methicillin-resistant S. aureus (MRSA), and Mycobacterium tuberculosis. (2E)-N-[3-Fluoro-4-(trifluoromethyl)phenyl]-3-phenylprop-2-enamide showed even better activity (minimum inhibitory concentration (MIC) 25.9 and 12.9 µM) against MRSA isolates than the commonly used ampicillin (MIC 45.8 µM). The screening of the cell viability was performed using THP1-Blue™ NF-κB cells and, except for (2E)-N-(4-bromo-3-chlorophenyl)-3-phenylprop-2-enamide (IC₅₀ 6.5 µM), none of the discussed compounds showed any significant cytotoxic effect up to 20 μM. Moreover, all compounds were tested for their anti-inflammatory potential; several compounds attenuated the lipopolysaccharide-induced NF-κB activation and were more potent than the parental cinnamic acid. The lipophilicity values were specified experimentally as well. In addition, in silico approximation of the lipophilicity values was performed employing a set of free/commercial clogP estimators, corrected afterwards by the corresponding pK_a calculated at physiological pH and subsequently cross-compared with the experimental parameters. The similarity-driven property space evaluation of structural analogs was carried out using the principal component analysis, Tanimoto metrics, and Kohonen mapping. Full article

(This article belongs to the Special Issue ECSOC-23)

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Figure 1
Effect of tested compounds on activity of transcription factor NF-κB. THP1-Blue™ NF-κB cells were pretreated by compounds (1 µM) dissolved in dimethyl sulfoxide (DMSO) for 1 h. Then, lipopolysaccharide (LPS) 1 µg/mL was added to trigger the NF-κB activation. The activity of NF-κB was measured 24 h after LPS stimulation using QuantiBlue™ assay. The graph represents mean ± SEM (n = 9). The red dotted line shows the value of the DMSO-only treated group. Groups were compared with the help of the one-way ANOVA test followed by Fisher’s LSD multiple comparison test. * indicates statistical significance (p < 0.05) to DMSO group; ** indicates statistical significance (p < 0.01) to DMSO group; *** indicates statistical significance (p < 0.001) to DMSO group; **** indicates statistical significance (p < 0.0001) to DMSO group. CA—cinnamic acid. Full article ">Figure 2
Projection of cinnamic acid anilides 1–20 on plane defined by first vs. second principal components for Dragon descriptors (a) with experimental logD7.4 (b). Colors code numerical values of logD at pH = 7.4. Full article ">Figure 3
Projection of cinnamic acid anilides 1–20 on a plane defined by first vs. second principal components for Dragon descriptors with Ro5 rule violations (a) and cytotoxic effect IC50 (b). Colors code numerical values of Ro5 violations and IC50. Full article ">Figure 4
Matrix of correlation coefficients of linear relationships between experimental and calculated logD7.4 lipophilicity specified using different programs. Full article ">Figure 5
Distribution of Tanimoto coefficients (a) and triangular matrix of Tanimoto coefficients (b) for 1–20 anilides. Full article ">Figure 6
Superimposition of 1–20 anilides according to AAA hypothesis. Full article ">Figure 7
Molecular electrostatic potential topography of 1–20 anilides. Blue color codes negative values; red color codes positive MESP values. Full article ">Figure 8
Comparative SOM 40 × 40 maps for 1–20 anilides. Colors code MESP values, white color indicates non-active neurons. Full article ">Scheme 1
Synthesis of ring-substituted (2E)-N-aryl-3-phenylprop-2-enamides 1–20. Reagents and conditions: (a) PCl3, chlorobenzene, MW (max. 500 W), 130 °C, 30 min [<a href="#B26-molecules-25-04121" class="html-bibr">26</a>,<a href="#B28-molecules-25-04121" class="html-bibr">28</a>]. Full article ">

32 pages, 4896 KiB

Open AccessArticle

Synthesis of Potential Haptens with Morphine Skeleton and Determination of Protonation Constants

by István Köteles, Károly Mazák, Gergő Tóth, Boglárka Tűz and Sándor Hosztafi

Molecules 2020, 25(17), 4009; https://doi.org/10.3390/molecules25174009 - 2 Sep 2020

Cited by 7 | Viewed by 5258

Abstract

Vaccination could be a promising alternative warfare against drug addiction and abuse. For this purpose, so-called haptens can be used. These molecules alone do not induce the activation of the immune system, this occurs only when they are attached to an immunogenic carrier [...] Read more.

Vaccination could be a promising alternative warfare against drug addiction and abuse. For this purpose, so-called haptens can be used. These molecules alone do not induce the activation of the immune system, this occurs only when they are attached to an immunogenic carrier protein. Hence obtaining a free amino or carboxylic group during the structural transformation is an important part of the synthesis. Namely, these groups can be used to form the requisite peptide bond between the hapten and the carrier protein. Focusing on this basic principle, six nor-morphine compounds were treated with ethyl acrylate and ethyl bromoacetate, while the prepared esters were hydrolyzed to obtain the N-carboxymethyl- and N-carboxyethyl-normorphine derivatives which are considered as potential haptens. The next step was the coupling phase with glycine ethyl ester, but the reactions did not work or the work-up process was not accomplishable. As an alternative route, the normorphine-compounds were N-alkylated with N-(chloroacetyl)glycine ethyl ester. These products were hydrolyzed in alkaline media and after the work-up process all of the derivatives contained the free carboxylic group of the glycine side chain. The acid-base properties of these molecules are characterized in detail. In the N-carboxyalkyl derivatives, the basicity of the amino and phenolate site is within an order of magnitude. In the glycine derivatives the basicity of the amino group is significantly decreased compared to the parent compounds (i.e., morphine, oxymorphone) because of the electron withdrawing amide group. The protonation state of the carboxylate group significantly influences the basicity of the amino group. All of the glycine ester and the glycine carboxylic acid derivatives are currently under biological tests. Full article

(This article belongs to the Special Issue ECSOC-23)

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13 pages, 2175 KiB

Open AccessArticle

Application of Natural Pigments in Ordinary Cooked Ham

by Sandra Dias, Elisabete M. S. Castanheira, A. Gil Fortes, David M. Pereira, A. Rita O. Rodrigues, Regina Pereira and M. Sameiro T. Gonçalves

Molecules 2020, 25(9), 2241; https://doi.org/10.3390/molecules25092241 - 10 May 2020

Cited by 11 | Viewed by 3594

Abstract

The possibility of obtaining a carmine or pink color on ordinary cooked ham by applying natural dyes from three plant species, namely red radish (Raphanus sativus L.), hibiscus (Roselle sabdariffa L.) and red beetroot (Beta vulgaris L.), was investigated. The [...] Read more.

The possibility of obtaining a carmine or pink color on ordinary cooked ham by applying natural dyes from three plant species, namely red radish (Raphanus sativus L.), hibiscus (Roselle sabdariffa L.) and red beetroot (Beta vulgaris L.), was investigated. The extracts were evaluated for the stability at physical-chemical parameters and subjected to cytotoxicity assays in the gastric cell line AGS Encapsulation of the extracts in soybean lecithin liposomes and maltodextrin microcapsules was performed. Lyophilized extracts before and after encapsulation in maltodextrin were applied in the formulation of ordinary cooked ham and used in a pilot scale of production. The color of cooked ham samples from different assays was evaluated visually and by colorimetry. The results suggest that the coloration of ordinary cooked ham obtained with extracts of red beetroot is very promising for future applications in this type of meat product. Full article

(This article belongs to the Special Issue ECSOC-23)

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Graphical abstract
Full article ">Figure 1
Absorption spectra of aqueous solutions of lyophilized extracts of red radish (concentration: 1.47 × 10−3 g/mL) and hibiscus (concentration: 1.73 × 10−3 g/mL). Inset: Expansion of the spectra in the visible region. Full article ">Figure 2
Absorption spectrum of red beetroot lyophilized extract in aqueous solution (at a concentration of 1.73 × 10−3 g/mL). Inset: Spectral decomposition in the visible region to obtain betacyanins and betaxanthins content. Full article ">Figure 3
Low resolution mass spectrum acquired in positive ionization mode (ESI) of red beetroot lyophilized extract with peaks at 550.78 (100.00 %) and 551.78 m/z (39.50%). Full article ">Figure 4
Viability of AGS cells exposed to red radish, hibiscus, and red beetroot extracts for 24 h, in the 31.25–500 µg/mL range. Full article ">Figure 5
Lyophilized extracts in water (A), (C), (E) and brine (B), (D), (F) of red radish (A), (B), hibiscus (C), (D), and red beetroot (E), (F). Full article ">Figure 6
Samples in slices from the pilot scale ordinary cooked ham (OCH) obtained without dye, with E120, and the non-encapsulated and encapsulated extracts of hibiscus and red beetroot with various concentrations. Full article ">Figure 7
Representation of the colors of the several samples in the L*a*b* color scheme. Full article ">

15 pages, 3457 KiB

Open AccessArticle

Simplified Procedure for General Synthesis of Monosubstituted Piperazines—From a Batch Reaction Vessel to a Flow (Microwave) Reactor

by Dana Němečková, Eva Havránková, Jan Šimbera, Richard Ševčík and Pavel Pazdera

Molecules 2020, 25(9), 2168; https://doi.org/10.3390/molecules25092168 - 6 May 2020

Cited by 1 | Viewed by 3462

Abstract

We reported a novel simplified synthetic procedure for the preparation of monosubstituted piperazine derivatives which can now be easily prepared in a one-pot-one-step way from a protonated piperazine with no need of introduction of a protecting group. Reactions, proceeding either at room or [...] Read more.

We reported a novel simplified synthetic procedure for the preparation of monosubstituted piperazine derivatives which can now be easily prepared in a one-pot-one-step way from a protonated piperazine with no need of introduction of a protecting group. Reactions, proceeding either at room or higher temperatures in common solvents, involve heterogeneous catalysis by metal ions supported on commercial polymeric resins. A general synthetic scheme was successfully applied to afford a wide range of monosubstituted piperazines. Furthermore, we picked up a set of piperazine derivatives and studied the possibilities of microwave acceleration of given synthetic reactions to make them even more efficient. Our research proceeded from a simple batch technique to the construction of a flow microwave reactor prototype and resulted in promising findings which are summarized and discussed in the article. Full article

(This article belongs to the Special Issue ECSOC-23)

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15 pages, 814 KiB

Open AccessArticle

Antioxidative Activity of 1,3,5-Triazine Analogues Incorporating Aminobenzene Sulfonamide, Aminoalcohol/Phenol, Piperazine, Chalcone, or Stilbene Motifs

by Eva Havránková, Nikola Čalkovská, Tereza Padrtová, Jozef Csöllei, Radka Opatřilová and Pavel Pazdera

Molecules 2020, 25(8), 1787; https://doi.org/10.3390/molecules25081787 - 14 Apr 2020

Cited by 11 | Viewed by 2886

Abstract

A series of 1,3,5-triazine analogues, incorporating aminobenzene sulfonamide, aminoalcohol/phenol, piperazine, chalcone, or stilbene structural motifs, were evaluated as potential antioxidants. The compounds were prepared by using step-by-step nucleophilic substitution of chlorine atoms in starting 2,4,6-trichloro-1,3,5-triazine. Reactions were catalyzed by Cu(I)-supported on a weakly [...] Read more.

A series of 1,3,5-triazine analogues, incorporating aminobenzene sulfonamide, aminoalcohol/phenol, piperazine, chalcone, or stilbene structural motifs, were evaluated as potential antioxidants. The compounds were prepared by using step-by-step nucleophilic substitution of chlorine atoms in starting 2,4,6-trichloro-1,3,5-triazine. Reactions were catalyzed by Cu(I)-supported on a weakly acidic resin. The radical scavenging activity was determined in terms of %inhibition activity and EC₅₀, using the ABTS method. Trolox and ascorbic acid (ASA) were used as standards. In the lowest concentration 1 × 10⁻⁴ M, the %inhibition activity values at 0 min were comparable with both standards at least for 10 compounds. After 60 min, compounds 5, 6, 13, and 25 showed nearly twice %inhibition (73.44–87.09%) in comparison with the standards (Trolox = 41.49%; ASA = 31.07%). Values of EC₅₀ at 60 min (17.16–27.78 μM) were 5 times lower for compounds 5, 6, 13, and 25 than EC₅₀ of both standards (trolox = 178.33 μM; ASA = 147.47 μM). Values of EC₅₀ correlated with %inhibition activity. Based on these results, the presented 1,3,5-triazine analogues have a high potential in the treatment of illnesses caused or related to oxidative stress. Full article

(This article belongs to the Special Issue ECSOC-23)

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13 pages, 3632 KiB

Open AccessArticle

Structure-Based Site of Metabolism (SOM) Prediction of Ligand for CYP3A4 Enzyme: Comparison of Glide XP and Induced Fit Docking (IFD)

by Deepak K. Lokwani, Aniket P. Sarkate, Kshipra S. Karnik, Anna Pratima G. Nikalje and Julio A. Seijas

Molecules 2020, 25(7), 1622; https://doi.org/10.3390/molecules25071622 - 1 Apr 2020

Cited by 13 | Viewed by 4176

Abstract

Metabolism is one of the prime reasons where most of drugs fail to accomplish their clinical trials. The enzyme CYP3A4, which belongs to the superfamily of cytochrome P450 enzymes (CYP), helps in the metabolism of a large number of drugs in the body. [...] Read more.

Metabolism is one of the prime reasons where most of drugs fail to accomplish their clinical trials. The enzyme CYP3A4, which belongs to the superfamily of cytochrome P450 enzymes (CYP), helps in the metabolism of a large number of drugs in the body. The enzyme CYP3A4 catalyzes oxidative chemical processes and shows a very broad range of ligand specificity. The understanding of the compound’s structure where oxidation would take place is crucial for the successful modification of molecules to avoid unwanted metabolism and to increase its bioavailability. For this reason, it is required to know the site of metabolism (SOM) of the compounds, where compounds undergo enzymatic oxidation. It can be identified by predicting the accessibility of the substrate’s atom toward oxygenated Fe atom of heme in a CYP protein. The CYP3A4 enzyme is highly flexible and can take significantly different conformations depending on the ligand with which it is being bound. To predict the accessibility of substrate atoms to the heme iron, conventional protein-rigid docking methods failed due to the high flexibility of the CYP3A4 protein. Herein, we demonstrated and compared the ability of the Glide extra precision (XP) and Induced Fit docking (IFD) tool of Schrodinger software suite to reproduce the binding mode of co-crystallized ligands into six X-ray crystallographic structures. We extend our studies toward the prediction of SOM for compounds whose experimental SOM is reported but the ligand-enzyme complex crystal structure is not available in the Protein Data Bank (PDB). The quality and accuracy of Glide XP and IFD was determined by calculating RMSD of docked ligands over the corresponding co-crystallized bound ligand and by measuring the distance between the SOM of the ligand and Fe atom of heme. It was observed that IFD reproduces the exact binding mode of available co-crystallized structures and correctly predicted the SOM of experimentally reported compounds. Our approach using IFD with multiple conformer structures of CYP3A4 will be one of the effective methods for SOM prediction. Full article

(This article belongs to the Special Issue ECSOC-23)

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Superimposition of three crystal structures of CYP3A4. Full article ">Figure 2
Superimposition of the pose of ketoconazole docked in (a) PDB id 1TQN and (b) PDB id 2V0M by IFD over crystal structure of ketoconazole bound CYP3A4 (PDB id 2V0M). The pink dotted line indicates the distance between site of metabolism (SOM) and the Fe atom of heme. Full article ">Figure 2 Cont.
Superimposition of the pose of ketoconazole docked in (a) PDB id 1TQN and (b) PDB id 2V0M by IFD over crystal structure of ketoconazole bound CYP3A4 (PDB id 2V0M). The pink dotted line indicates the distance between site of metabolism (SOM) and the Fe atom of heme. Full article ">Figure 3
Chemical Structures of compounds. Red color indicates experimentally reported major SOM. Full article ">Figure 4
Superimposition of the IFD docking pose of ligands in CYP3A4 enzyme (a) Alprazolam (1W0E-1W0G)-Site 1, (b) Alprazolam (1W0E-1W0G)-Site 2, (c) Nevirapine (1W0F-3NXU), and (d) Tamoxifen (1W0G-1TQN). The pink dotted line indicates the distance between SOM and the heme Fe atom. Full article ">Figure 4 Cont.
Superimposition of the IFD docking pose of ligands in CYP3A4 enzyme (a) Alprazolam (1W0E-1W0G)-Site 1, (b) Alprazolam (1W0E-1W0G)-Site 2, (c) Nevirapine (1W0F-3NXU), and (d) Tamoxifen (1W0G-1TQN). The pink dotted line indicates the distance between SOM and the heme Fe atom. Full article ">

24 pages, 5443 KiB

Open AccessArticle

An Improved Synthesis of Key Intermediate to the Formation of Selected Indolin-2-Ones Derivatives Incorporating Ultrasound and Deep Eutectic Solvent (DES) Blend of Techniques, for Some Biological Activities and Molecular Docking Studies

by Mohd Imran, Md. Afroz Bakht, Abida Khan, Md. Tauquir Alam, El Hassane Anouar, Mohammed B. Alshammari, Noushin Ajmal, Archana Vimal, Awanish Kumar and Yassine Riadi

Molecules 2020, 25(5), 1118; https://doi.org/10.3390/molecules25051118 - 2 Mar 2020

Cited by 5 | Viewed by 4065

Abstract

We have developed a new idea to synthesize a key intermediate molecule by utilizing deep eutectic solvent (DES) and ultrasound in a multistep reaction to ensure process cost-effectiveness. To confirm the stability of reagents with DES, electronic energies were calculated at the B3LYP/6-31+G(d,p) [...] Read more.

We have developed a new idea to synthesize a key intermediate molecule by utilizing deep eutectic solvent (DES) and ultrasound in a multistep reaction to ensure process cost-effectiveness. To confirm the stability of reagents with DES, electronic energies were calculated at the B3LYP/6-31+G(d,p) level of theory. DES stabilized the reagents mainly due to strong intermolecular hydrogen bonding. Key intermediate (3) and final compounds (4a–n) were synthesized in a higher yield of 95% and 80%–88%, respectively. Further, final compounds (4a–n) were assessed for their anti-inflammatory, analgesic, ulcerogenic, and lipid peroxidation. The compounds 4f, 4g, 4j, 4l, and 4m showed good anti-inflammatory activity, while 4f, 4i, and 4n exhibited very good analgesic activity as compared to the standard drug. The ulcerogenicity of selected compounds was far less than the indomethacin. The ligands had also shown a good docking score (4f = −6.859 kcal/mol and 4n = −7.077 kcal/mol) as compared to control indomethacin (−6.109 kcal/mol) against the target protein COX-2. These derivatives have the potential to block this enzyme and can be used as NSAID. The state-of-art DFT theory was used to validate the lipid peroxidation mechanism of the active compounds which was in good agreement with the variations of BDEs and IP of the tested compounds. Full article

(This article belongs to the Special Issue ECSOC-23)

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11 pages, 1989 KiB

Open AccessArticle

Antimicrobial, Antioxidant, and Anticancer Activities of Some Novel Isoxazole Ring Containing Chalcone and Dihydropyrazole Derivatives

by Afzal Shaik, Richie R. Bhandare, Kishor Palleapati, Srinath Nissankararao, Venkata Kancharlapalli and Shahanaaz Shaik

Molecules 2020, 25(5), 1047; https://doi.org/10.3390/molecules25051047 - 26 Feb 2020

Cited by 94 | Viewed by 7638

Abstract

Our previous work identified isoxazole-based chalcones and their dihydropyrazole derivatives as two important five-membered heterocycles having antitubercular activity. Hence, in the present study, we biologically evaluated 30 compounds, including 15 isoxazole ring-containing chalcones (17–31) and 15 dihydropyrazoles (32 [...] Read more.

Our previous work identified isoxazole-based chalcones and their dihydropyrazole derivatives as two important five-membered heterocycles having antitubercular activity. Hence, in the present study, we biologically evaluated 30 compounds, including 15 isoxazole ring-containing chalcones (17–31) and 15 dihydropyrazoles (32–46) derived from these chalcones for their antimicrobial, antioxidant, and anticancer activities. Chalcones exhibited superior antibacterial and antioxidant activities compared to dihydropyrazoles. Among the chalcones, compound 28 showed potent antibacterial (MIC = 1 µg/mL) and antioxidant activities (IC₅₀ = 5 ± 1 µg/mL). Dihydropyrazoles, on the contrary, demonstrated remarkable antifungal and anticancer activities. Compound 46 (IC₅₀ = 2 ± 1 µg/mL) showed excellent antifungal activity whereas two other dihydropyrazoles 45 (IC₅₀ = 2 ± 1 µg/mL) and 39 (IC₅₀ = 4 ± 1 µg/mL) exhibited potential anticancer activity. The compounds were also tested for their toxicity on normal human cell lines (LO2) and were found to be nontoxic. The active compounds that have emerged out of this study are potential lead molecules for the development of novel drugs against infectious diseases, oxidative stress, and cancer. Full article

(This article belongs to the Special Issue ECSOC-23)

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17 pages, 1633 KiB

Open AccessFeature PaperArticle

Extraction and Physicochemical Characterization of Chitin Derived from the Asian Hornet, Vespa velutina Lepeletier 1836 (Hym.: Vespidae)

by Xesús Feás, M. Pilar Vázquez-Tato, Julio A. Seijas, Anna Pratima G. Nikalje and Francisco Fraga-López

Molecules 2020, 25(2), 384; https://doi.org/10.3390/molecules25020384 - 17 Jan 2020

Cited by 24 | Viewed by 5981

Abstract

Fifteen years ago, at least one multimated female yellow-legged Asian hornet (Vespa velutina Lepeletier 1836) arrived in France, which gave rise to a pan-European invasion. In this study, the isolation and characterization of chitin (CHI) that was obtained from Vespa velutina (CHI [...] Read more.

Fifteen years ago, at least one multimated female yellow-legged Asian hornet (Vespa velutina Lepeletier 1836) arrived in France, which gave rise to a pan-European invasion. In this study, the isolation and characterization of chitin (CHI) that was obtained from Vespa velutina (CHI_VV) is described. In addition, an easy procedure is carried out to capture the raw insect, selectively and with high rates of success. The chitin contents of dry VV was observed to be 11.7%. Fourier transform infrared spectroscopy (FTIR), solid-state NMR (ssNMR), elemental analysis (EA), scanning electron microscopy (SEM), and thermogravimetric analysis (TG) characterized the physicochemical properties of CHI_VV. The obtained CHI_VV is close to pure (43.47% C, 6.94% H, and 6.85% N), and full acetylated with a value of 95.44%. Additionally, lifetime and kinetic parameters such as activation E and the frequency factor A using model-free and model-fitting methods, were determined. For CHI_VV the solid state mechanism that follows the thermodegradation is of type F2 (random nucleation around two nuclei). The invasive Asian hornet is a promising alternative source of CHI, based on certain factors, such as the current and probable continued abundance of the quantity and quality of the product obtained. Full article

(This article belongs to the Special Issue ECSOC-23)

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