Molecules

Research

26 pages, 4165 KiB

Open AccessArticle

Synthesis and Structure-Activity Relationship Studies of Hydrazide-Hydrazones as Inhibitors of Laccase from Trametes versicolor

by Halina Maniak, Michał Talma, Konrad Matyja, Anna Trusek and Mirosław Giurg

Molecules 2020, 25(5), 1255; https://doi.org/10.3390/molecules25051255 - 10 Mar 2020

Cited by 25 | Viewed by 8153

Abstract

A series of hydrazide-hydrazones 1–3, the imine derivatives of hydrazides and aldehydes bearing benzene rings, were screened as inhibitors of laccase from Trametes versicolor. Laccase is a copper-containing enzyme which inhibition might prevent or reduce the activity of the plant pathogens [...] Read more.

A series of hydrazide-hydrazones 1–3, the imine derivatives of hydrazides and aldehydes bearing benzene rings, were screened as inhibitors of laccase from Trametes versicolor. Laccase is a copper-containing enzyme which inhibition might prevent or reduce the activity of the plant pathogens that produce it in various biochemical processes. The kinetic and molecular modeling studies were performed and for selected compounds, the docking results were discussed. Seven 4-hydroxybenzhydrazide (4-HBAH) derivatives exhibited micromolar activity K_i = 24–674 µM with the predicted and desirable competitive type of inhibition. The structure–activity relationship (SAR) analysis revealed that a slim salicylic aldehyde framework had a pivotal role in stabilization of the molecules near the substrate docking site. Furthermore, the presence of phenyl and bulky tert-butyl substituents in position 3 in salicylic aldehyde fragment favored strong interaction with the substrate-binding pocket in laccase. Both 3- and 4-HBAH derivatives containing larger 3-tert-butyl-5-methyl- or 3,5-di-tert-butyl-2-hydroxy-benzylidene unit, did not bind to the active site of laccase and, interestingly, acted as non-competitive (K_i = 32.0 µM) or uncompetitive (K_i = 17.9 µM) inhibitors, respectively. From the easily available laccase inhibitors only sodium azide, harmful to environment and non-specific, was over 6 times more active than the above compounds. Full article

(This article belongs to the Special Issue New Studies on the Synthesis of Biologically Active Products)

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11 pages, 1318 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of Aromatic Amide-Substituted Benzimidazole-Derived Chalcones. The Effect of Upregulating TP53 Protein Expression

by Lintao Wu, Yuting Yang, Zhijun Wang, Xi Wu, Feng Su, Mengyao Li, Xiaobi Jing and Chun Han

Molecules 2020, 25(5), 1162; https://doi.org/10.3390/molecules25051162 - 5 Mar 2020

Cited by 2 | Viewed by 2838

Abstract

A series of benzimidazole-derived chalcones containing aromatic amide substituent were designed and synthesized. All of the chalcone compounds were tested for their in vitro antitumor activity against human cancer cell lines (HCT116, HepG2, A549, and CRL-5908). The antiproliferative activity of compounds 3, [...] Read more.

A series of benzimidazole-derived chalcones containing aromatic amide substituent were designed and synthesized. All of the chalcone compounds were tested for their in vitro antitumor activity against human cancer cell lines (HCT116, HepG2, A549, and CRL-5908). The antiproliferative activity of compounds 3, 6, 9, 14, 15, 16 against HCT116 cells was significantly better than that that of 5-Fluorouracil (IC50: 94.63 µM). The antitumor activity of these compounds showed obvious differences between the wild type HCT116 and mutant HCT116 (TP53^−/−) cells. A preliminary mechanistic study suggested that these compounds act by upregulating the expression of TP53 protein in tumor cells without inhibiting the MDM2-TP53 interaction. Full article

(This article belongs to the Special Issue New Studies on the Synthesis of Biologically Active Products)

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11 pages, 2526 KiB

Open AccessArticle

Synthesis of the Novel Covalent Cysteine Proteases Inhibitor with Iodoacetic Functional Group

by Kinga Hartman, Przemyslaw Mielczarek and Jerzy Silberring

Molecules 2020, 25(4), 813; https://doi.org/10.3390/molecules25040813 - 13 Feb 2020

Cited by 5 | Viewed by 3650

Abstract

This work presents the synthesis of the novel covalent inhibitor of cysteine proteases where epoxide has been replaced by the iodoacetyl functional group. The molecule, similar in action to E-64 and DCG-04, the commonly applied inhibitors, is additionally biotinylated and contains tyrosyl iodination [...] Read more.

This work presents the synthesis of the novel covalent inhibitor of cysteine proteases where epoxide has been replaced by the iodoacetyl functional group. The molecule, similar in action to E-64 and DCG-04, the commonly applied inhibitors, is additionally biotinylated and contains tyrosyl iodination sites. The Fmoc solid phase synthesis has been applied. Conjugation of iodoacetic acid with the peptide was optimized by testing different conjugation agents. The purity of the final product was verified by mass spectrometry and its bioactivity was tested by incubation with a model cysteine protease—staphopain C. Finally, it was shown that the synthesized inhibitor binds to the protein at the ratio of 1:1. More detailed analysis by means of tandem mass spectrometry proved that the inhibitor binds to the cysteine present in the active site of the enzyme. Full article

(This article belongs to the Special Issue New Studies on the Synthesis of Biologically Active Products)

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25 pages, 9013 KiB

Open AccessArticle

Synthesis, Biological Assessment, and Structure Activity Relationship Studies of New Flavanones Embodying Chromene Moieties

by Eman Assirey, Azhaar Alsaggaf, Arshi Naqvi, Ziad Moussa, Rawda M. Okasha, Tarek H. Afifi and Alaa S. Abd-El-Aziz

Molecules 2020, 25(3), 544; https://doi.org/10.3390/molecules25030544 - 27 Jan 2020

Cited by 14 | Viewed by 4190

Abstract

Novel flavanones that incorporate chromene motifs are synthesized via a one-step multicomponent reaction. The structures of the new chromenes are elucidated by using IR, ¹H-NMR, ¹³C-NMR, ¹H-¹H COSY, HSQC, HMBC, and elemental analysis. The new compounds are screened [...] Read more.

Novel flavanones that incorporate chromene motifs are synthesized via a one-step multicomponent reaction. The structures of the new chromenes are elucidated by using IR, ¹H-NMR, ¹³C-NMR, ¹H-¹H COSY, HSQC, HMBC, and elemental analysis. The new compounds are screened for their in vitro antimicrobial and cytotoxic activities. The antimicrobial properties are investigated and established against seven human pathogens, employing the agar well diffusion method and the minimum inhibitory concentrations. A majority of the assessed derivatives are found to exhibit significant antimicrobial activities against most bacterial strains, in comparison to standard reference drugs. Moreover, their cytotoxicity is appraised against four different human carcinoma cell lines: human colon carcinoma (HCT-116), human hepatocellular carcinoma (HepG-2), human breast adenocarcinoma (MCF-7), and adenocarcinoma human alveolar basal epithelial cell (A-549). All the desired compounds are subjected to in-silico studies, forecasting their drug likeness, bioactivity, and the absorption, distribution, metabolism, and excretion (ADME) properties prior to their synthetic assembly. The in-silico molecular docking evaluation of all the targeted derivatives is undertaken on gyrase B and the cyclin-dependent kinase. The in-silico predicted outcomes were endorsed by the in vitro studies. Full article

(This article belongs to the Special Issue New Studies on the Synthesis of Biologically Active Products)

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20 pages, 1386 KiB

Open AccessArticle

Characterization of Antimicrobial, Antioxidant, and Leishmanicidal Activities of Schiff Base Derivatives of 4-Aminoantipyrine

by Rommy Teran, Rommel Guevara, Jessica Mora, Lizeth Dobronski, Olalla Barreiro-Costa, Timo Beske, Jorge Pérez-Barrera, Ramiro Araya-Maturana, Patricio Rojas-Silva, Ana Poveda and Jorge Heredia-Moya

Molecules 2019, 24(15), 2696; https://doi.org/10.3390/molecules24152696 - 24 Jul 2019

Cited by 52 | Viewed by 6646

Abstract

Our main interest is the characterization of compounds to support the development of alternatives to currently marketed drugs that are losing effectiveness due to the development of resistance. Schiff bases are promising biologically interesting compounds having a wide range of pharmaceutical properties, including [...] Read more.

Our main interest is the characterization of compounds to support the development of alternatives to currently marketed drugs that are losing effectiveness due to the development of resistance. Schiff bases are promising biologically interesting compounds having a wide range of pharmaceutical properties, including anti-inflammatory, antipyretic, and antimicrobial activities, among others. In this work, we have synthesized 12 Schiff base derivatives of 4-aminoantipyrine. In vitro antimicrobial, antioxidant, and cytotoxicity properties are analyzed, as well as in silico predictive adsorption, distribution, metabolism, and excretion (ADME) and bioactivity scores. Results identify two potential Schiff bases: one effective against E. faecalis and the other with antioxidant activity. Both have reasonable ADME scores and provides a scaffold for developing more effective compounds in the future. Initial studies are usually limited to laboratory in vitro approaches, and following these initial studies, much research is needed before a drug can reach the clinic. Nevertheless, these laboratory approaches are mandatory and constitute a first filter to discriminate among potential drug candidates and chemical compounds that should be discarded. Full article

(This article belongs to the Special Issue New Studies on the Synthesis of Biologically Active Products)

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23 pages, 1642 KiB

Open AccessArticle

New γ-Halo-δ-lactones and δ-Hydroxy-γ-lactones with Strong Cytotoxic Activity

by Angelika Kamizela, Barbara Gawdzik, Mariusz Urbaniak, Łukasz Lechowicz, Agata Białońska, Sylwia Ewa Kutniewska, Weronika Gonciarz and Magdalena Chmiela

Molecules 2019, 24(10), 1875; https://doi.org/10.3390/molecules24101875 - 15 May 2019

Cited by 9 | Viewed by 3612

Abstract

This paper presents the synthesis of

γ

-halo-

δ

-lactones,

δ

-iodo-

γ

-lactones and

δ

-hydroxy-

γ

-lactones from readily available organic substrates such as trans-crotonaldehyde and aryl bromides. Crystal structure analysis was carried out for lactones that were obtained in [...] Read more.

This paper presents the synthesis of

γ

-halo-

δ

-lactones,

δ

-iodo-

γ

-lactones and

δ

-hydroxy-

γ

-lactones from readily available organic substrates such as trans-crotonaldehyde and aryl bromides. Crystal structure analysis was carried out for lactones that were obtained in crystalline form. All halo-

δ

-lactones and

δ

-hydroxy-

γ

-lactones were highly cytotoxic against gastric cancer AGS cells with

I C_{50}

values in the range of 0.0006–0.0044 mM. Some lactones showed high bactericidal activity against E. coli ATCC 8739 and S. aureus ATCC 65389, which reduced the number of CFU/mL by 70–83% and 87% respectively. Full article

(This article belongs to the Special Issue New Studies on the Synthesis of Biologically Active Products)

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13 pages, 3822 KiB

Open AccessArticle

A Simple and Efficient Method for the Partial Synthesis of Pure (3R,3’S)-Astaxanthin from (3R,3’R,6’R)-Lutein and Lutein Esters via (3R,3’S)-Zeaxanthin and Theoretical Study of Their Formation Mechanisms

by Eloy Rodríguez-deLeón, J. Oscar. C. Jiménez-Halla, José E. Báez and M. Moustapha Bah

Molecules 2019, 24(7), 1386; https://doi.org/10.3390/molecules24071386 - 9 Apr 2019

Cited by 9 | Viewed by 5045

Abstract

Carotenoids are natural compounds that have important roles in promoting and maintaining human health. Synthetic astaxanthin is a highly requested product by the aquaculture industry, but natural astaxanthin is not. Various strategies have been developed to synthesize this carotenoid. Nonetheless, these approaches have [...] Read more.

Carotenoids are natural compounds that have important roles in promoting and maintaining human health. Synthetic astaxanthin is a highly requested product by the aquaculture industry, but natural astaxanthin is not. Various strategies have been developed to synthesize this carotenoid. Nonetheless, these approaches have not only provided limited global yields, but its main commercial source also carries several health risks for humans. In this contribution, the one-pot base-catalyzed reaction of (3R,3’R,6’R)-lutein (1) esters has resulted in a successful isomerization process to easily obtain up to 95% meso-zeaxanthin (2), which in turn is oxidized to (3R,3’S)-astaxanthin (3) with a global yield of 68%. The same oxidation performed with UV irradiation (365 nm) for 5 min provided the highest global yield (76%). These chemical transformations have also been achieved with a significant reduction of the health risks associated with its potential human consumption. Furthermore, this is the first time only one of the configurational isomers has been obtained semisynthetically. The poorly understood formation mechanisms of these two compounds were also investigated using Density-Functional Theory (DFT) calculations. These theoretical studies revealed that the isomerization involves a base-catalyzed deprotonation at C-6’, followed by C-4’ protonation, while the oxidation occurs via free radical mechanisms. Full article

(This article belongs to the Special Issue New Studies on the Synthesis of Biologically Active Products)

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13 pages, 1128 KiB

Open AccessArticle

An Improved Method for the Quaternization of Nicotinamide and Antifungal Activities of Its Derivatives

by Tamara Siber, Valentina Bušić, Dora Zobundžija, Sunčica Roca, Dražen Vikić-Topić, Karolina Vrandečić and Dajana Gašo-Sokač

Molecules 2019, 24(6), 1001; https://doi.org/10.3390/molecules24061001 - 13 Mar 2019

Cited by 14 | Viewed by 4256

Abstract

The quaternization reactions of nicotinamide, with different electrophiles: methyl iodide and substituted 2-bromoacetophenones (4-Cl, 4-Br, 4-H, 4-CH₃, 4-F, 4-OCH₃, 4-Ph, 2-OCH₃, 4-NO₂) are reported. The preparations were carried out by conventional synthesis and under microwave [...] Read more.

The quaternization reactions of nicotinamide, with different electrophiles: methyl iodide and substituted 2-bromoacetophenones (4-Cl, 4-Br, 4-H, 4-CH₃, 4-F, 4-OCH₃, 4-Ph, 2-OCH₃, 4-NO₂) are reported. The preparations were carried out by conventional synthesis and under microwave irradiation in absolute ethanol and acetone. The synthesis performed by microwave dielectric heating significantly improved yield, up to 8 times, and shortened down the reaction time from ca. one day in conventional, to 10–20 min. The structures of the synthesized compounds were confirmed by IR, ¹H- and ¹³C-NMR spectroscopy, mass spectrometry and elemental analysis. The compounds have been screened for antifungal activities against Fusarium oxysporum, Fusarium culmorum, Macrophomina phaseolina and Sclerotinia sclerotiorum at concentrations of 10 µg/mL and 100 µg/mL. Six compounds showed the strong inhibition of mycelium growth at a concentration of 10 µg/mL. All tested compounds revealed the great inhibitory activities against S. sclerotiorum at a concentration of 100 µg/mL. Full article

(This article belongs to the Special Issue New Studies on the Synthesis of Biologically Active Products)

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11 pages, 3115 KiB

Open AccessCommunication

Convenient Synthesis of Functionalized Cyclopropa[c]coumarin-1a-carboxylates

by Olga A. Ivanova, Vladimir A. Andronov, Irina I. Levina, Alexey O. Chagarovskiy, Leonid G. Voskressensky and Igor V. Trushkov

Molecules 2019, 24(1), 57; https://doi.org/10.3390/molecules24010057 - 24 Dec 2018

Cited by 10 | Viewed by 3592

Abstract

A simple method has been developed for the synthesis of cyclopropa[c]coumarins, which belong to the donor-acceptor cyclopropane family and, therefore, are promising substrates for the preparation of chromene-based fine chemicals. The method, based on the acetic acid-induced intramolecular transesterification of 2-arylcyclopropane-1,1-dicarboxylates, [...] Read more.

A simple method has been developed for the synthesis of cyclopropa[c]coumarins, which belong to the donor-acceptor cyclopropane family and, therefore, are promising substrates for the preparation of chromene-based fine chemicals. The method, based on the acetic acid-induced intramolecular transesterification of 2-arylcyclopropane-1,1-dicarboxylates, was found to be efficient for substrates containing hydroxy group directly attached to the aromatic ring. Full article

(This article belongs to the Special Issue New Studies on the Synthesis of Biologically Active Products)

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