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Special Issue “Structure–Activity Relationship of Natural Products”

by Jean-Marc Sabatier

Molecules 2017, 22(5), 697; https://doi.org/10.3390/molecules22050697 - 27 Apr 2017

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This Special Issue of Molecules deals with the structure–activity relationship of natural compounds which possess some pharmacological/chemical properties of potential interest (from basic research to the clinical applications) in a wide range of areas, such as bacteriology, parasitology, cancerology, inflammation, etc.[...] Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products)

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1386 KiB

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Structure-Activity and Lipophilicity Relationships of Selected Antibacterial Natural Flavones and Flavanones of Chilean Flora

by Javier Echeverría, Julia Opazo, Leonora Mendoza, Alejandro Urzúa and Marcela Wilkens

Molecules 2017, 22(4), 608; https://doi.org/10.3390/molecules22040608 - 10 Apr 2017

Cited by 96 | Viewed by 7177

Abstract

In this study, we tested eight naturally-occurring flavonoids—three flavanones and five flavones—for their possible antibacterial properties against four Gram-positive and four Gram-negative bacteria. Flavonoids are known for their antimicrobial properties, and due their structural diversity; these plant-derived compounds are a good model to [...] Read more.

In this study, we tested eight naturally-occurring flavonoids—three flavanones and five flavones—for their possible antibacterial properties against four Gram-positive and four Gram-negative bacteria. Flavonoids are known for their antimicrobial properties, and due their structural diversity; these plant-derived compounds are a good model to study potential novel antibacterial mechanisms. The lipophilicity and the interaction of antibacterial compounds with the cell membrane define the success or failure to access its target. Therefore, through the determination of partition coefficients in a non-polar/aqueous phase, lipophilicity estimation and the quantification of the antibacterial activity of different flavonoids, flavanones, and flavones, a relationship between these parameters was assessed. Active flavonoids presented diffusion coefficients between 9.4 × 10⁻¹⁰ and 12.3 × 10⁻¹⁰ m²/s and lipophilicity range between 2.0 to 3.3. Active flavonoids against Gram-negative bacteria showed a narrower range of lipophilicity values, compared to active flavonoids against Gram-positive bacteria, which showed a wide range of lipophilicity and cell lysis. Galangin was the most active flavonoid, whose structural features are the presence of two hydroxyl groups located strategically on ring A and the absence of polar groups on ring B. Methylation of one hydroxyl group decreases the activity in 3-O-methylgalangin, and methylation of both hydroxyl groups caused inactivation, as shown for 3,7-O-dimethylgalangin. In conclusion, the amphipathic features of flavonoids play a crucial role in the antibacterial activity. In these compounds, hydrophilic and hydrophobic moieties must be present and could be predicted by lipophilicity analysis. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products)

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1222 KiB

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The Structure–Antioxidant Activity Relationship of Ferulates

by Magdalena Karamać, Lidiya Koleva, Vessela D. Kancheva and Ryszard Amarowicz

Molecules 2017, 22(4), 527; https://doi.org/10.3390/molecules22040527 - 25 Mar 2017

Cited by 34 | Viewed by 6646

Abstract

The antioxidant activity of ferulic acid (1), iso-ferulic acid (2), coniferyl aldehyde (3), methyl ferulate (4), and ethyl ferulate (5) were investigated using 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and ferric-reducing antioxidant power (FRAP) assays [...] Read more.

The antioxidant activity of ferulic acid (1), iso-ferulic acid (2), coniferyl aldehyde (3), methyl ferulate (4), and ethyl ferulate (5) were investigated using 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and ferric-reducing antioxidant power (FRAP) assays and autoxidation of triacylglycerols of commercially available sunflower oil (TGSO). The compounds tested for ability to scavenge ABTS radical cations was in the order of ferulic acid > coniferyl aldehyde ≈ iso-ferulic acid > ethyl ferulate ≈ methyl ferulate. The results of the FRAP assay for ferulic acid, iso-ferulic acid, and coniferyl aldehyde were similar to and higher than those of methyl ferulate and ethyl ferulate. In the lipid system, iso-ferulic acid showed weak antioxidant activity. The other ferulates exhibited much stronger, yet similar, activities. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products)

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Open AccessArticle

Antiprotozoal Activity of Triazole Derivatives of Dehydroabietic Acid and Oleanolic Acid

by Mariano Walter Pertino, Celeste Vega, Miriam Rolón, Cathia Coronel, Antonieta Rojas de Arias and Guillermo Schmeda-Hirschmann

Molecules 2017, 22(3), 369; https://doi.org/10.3390/molecules22030369 - 28 Feb 2017

Cited by 27 | Viewed by 5391

Abstract

Tropical parasitic diseases such as Chagas disease and leishmaniasis are considered a major public health problem affecting hundreds of millions of people worldwide. As the drugs currently used to treat these diseases have several disadvantages and side effects, there is an urgent need [...] Read more.

Tropical parasitic diseases such as Chagas disease and leishmaniasis are considered a major public health problem affecting hundreds of millions of people worldwide. As the drugs currently used to treat these diseases have several disadvantages and side effects, there is an urgent need for new drugs with better selectivity and less toxicity. Structural modifications of naturally occurring and synthetic compounds using click chemistry have enabled access to derivatives with promising antiparasitic activity. The antiprotozoal activity of the terpenes dehydroabietic acid, dehydroabietinol, oleanolic acid, and 34 synthetic derivatives were evaluated against epimastigote forms of Trypanosoma cruzi and promastigotes of Leishmaniabraziliensis and Leishmania infantum. The cytotoxicity of the compounds was assessed on NCTC-Clone 929 cells. The activity of the compounds was moderate and the antiparasitic effect was associated with the linker length between the diterpene and the triazole in dehydroabietinol derivatives. For the oleanolic acid derivatives, a free carboxylic acid function led to better antiparasitic activity. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products)

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An Investigation on the Quantitative Structure-Activity Relationships of the Anti-Inflammatory Activity of Diterpenoid Alkaloids

by Xiao Li, Ning Li, Zhenyu Sui, Kaishun Bi and Zuojing Li

Molecules 2017, 22(3), 363; https://doi.org/10.3390/molecules22030363 - 27 Feb 2017

Cited by 12 | Viewed by 5607

Abstract

Diterpenoid alkaloids are extracted from plants. These compounds have broad biological activities, including effects on the cardiovascular system, anti-inflammatory and analgesic actions, and anti-tumor activity. The anti-inflammatory activity was determined by carrageenan-induced rat paw edema and experimental trauma in rats. The number of [...] Read more.

Diterpenoid alkaloids are extracted from plants. These compounds have broad biological activities, including effects on the cardiovascular system, anti-inflammatory and analgesic actions, and anti-tumor activity. The anti-inflammatory activity was determined by carrageenan-induced rat paw edema and experimental trauma in rats. The number of studies focused on the determination, quantitation and pharmacological properties of these alkaloids has increased dramatically during the past few years. In this work we built a dataset composed of 15 diterpenoid alkaloid compounds with diverse structures, of which 11 compounds were included in the training set and the remaining compounds were included in the test set. The quantitative chemistry parameters of the 15 diterpenoid alkaloids compound were calculated using the HyperChem software, and the quantitative structure–activity relationship (QSAR) of these diterpenoid alkaloid compounds were assessed in an anti-inflammation model based on half maximal effective concentration (EC₅₀) measurements obtained from rat paw edema data. The QSAR prediction model is as follows:

\log (E C_{50}) = - 0.0260 \times SAA + 0.0086 \times SAG + 0.0011 \times VOL - 0.0641 \times HE - 0.2628 \times LogP - 0.5594 \times REF - 0.2211 \times POL - 0.1964 \times MASS + 0.088 \times BE + 0.1398 \times HF

(R² = 0.981, Q² = 0.92). The validated consensus EC₅₀ for the QSAR model, developed from the rat paw edema anti-inflammation model used in this study, indicate that this model was capable of effective prediction and can be used as a reliable computational predictor of diterpenoid alkaloid activity. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products)

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23815 KiB

Open AccessArticle

The Structure-Activity Relationship of Pterostilbene Against Candida albicans Biofilms

by Dan-Dan Hu, Ri-Li Zhang, Yong Zou, Hua Zhong, En-Sheng Zhang, Xiang Luo, Yan Wang and Yuan-Ying Jiang

Molecules 2017, 22(3), 360; https://doi.org/10.3390/molecules22030360 - 27 Feb 2017

Cited by 13 | Viewed by 5052

Abstract

Candida albicans biofilms contribute to invasive infections and dramatic drug resistance, and anti-biofilm agents are urgently needed in the clinic. Pterostilbene (PTE) is a natural plant product with potentials to be developed as an anti-biofilm agent. In this study, we evaluated the structure-activity [...] Read more.

Candida albicans biofilms contribute to invasive infections and dramatic drug resistance, and anti-biofilm agents are urgently needed in the clinic. Pterostilbene (PTE) is a natural plant product with potentials to be developed as an anti-biofilm agent. In this study, we evaluated the structure-activity relationship (SAR) of PTE analogues against C. albicans biofilms. XTT (Sodium 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt) reduction assay was used to evaluate the activity of the analogues against C. albicans biofilms. Knowing that hyphal formation is essential for C. albicans biofilms, anti-hyphal assay was further carried out. By comparing a series of compounds tested in this study, we found that compounds with para-hydroxy (–OH) in partition A exhibited better activity than those with other substituents in the para position, and the double bond in partition B and meta-dimethoxy (–OCH₃) in partition C both contributed to the best activity. Consistent results were obtained by anti-hyphal assay. Collectively, para-hydroxy (–OH), double bond and meta-dimethoxy (–OCH₃) are all needed for the best activity of PTE against C. albicans biofilms. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products)

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Open AccessArticle

Structure-Antioxidative and Anti-Inflammatory Activity Relationships of Purpurin and Related Anthraquinones in Chemical and Cell Assays

by Woo Nam, Sung Phil Kim, Seok Hyun Nam and Mendel Friedman

Molecules 2017, 22(2), 265; https://doi.org/10.3390/molecules22020265 - 10 Feb 2017

Cited by 49 | Viewed by 6927

Abstract

Anthraquinone (9,10-anthraquinone) and several hydroxy derivatives, including purpurin (1,2,4-trihydroxyanthraquinone), anthrarufin (1,5-dihydroxyanthraquinone), and chrysazin (1,8-dihydroxyanthraquinone), were evaluated for antioxidative and anti-inflammatory activities in chemical assays and mammalian cells (murine macrophage RAW 264.7 cells). Several tests were used to assess their activities: 1,1-diphenyl-2-picrylhydrazyl (DPPH) free [...] Read more.

Anthraquinone (9,10-anthraquinone) and several hydroxy derivatives, including purpurin (1,2,4-trihydroxyanthraquinone), anthrarufin (1,5-dihydroxyanthraquinone), and chrysazin (1,8-dihydroxyanthraquinone), were evaluated for antioxidative and anti-inflammatory activities in chemical assays and mammalian cells (murine macrophage RAW 264.7 cells). Several tests were used to assess their activities: 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical; ABTS radical cation; hydrogen peroxide scavenging; reduction of potassium ferricyanide; chelation of ferrous ions; inhibition of lipid peroxidation; inhibition of nitric oxide generation; scavenging of the intracellular hydroxyl radical; expression of NLRP3 polypeptide for inflammasome assembly; and quantitation of proinflammatory cytokine interleukin 1β (IL-1β) for inflammasome activation. The results show that purpurin, from the root of the madder plant (Rubia tinctorum L.), exhibited the highest antioxidative activity in both chemical and cultured cell antioxidant assays. The antioxidative activities of the other three anthraquinones were lower than that of purpurin. In addition, purpurin could down-regulate NLRP3 inflammasome assembly and activation, suggesting that it might protect foods against oxidative damage and prevent in vivo oxidative stress and inflammation. Structure-activity relationships and the significance of the results for food quality and human health are discussed. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products)

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3585 KiB

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Phloretin Exerts Anti-Tuberculosis Activity and Suppresses Lung Inflammation

by Dasom Jeon, Min-Cheol Jeong, Hum Nath Jnawali, Chulhee Kwak, Sungwon Ryoo, In Duk Jung and Yangmee Kim

Molecules 2017, 22(1), 183; https://doi.org/10.3390/molecules22010183 - 22 Jan 2017

Cited by 23 | Viewed by 6964

Abstract

An increase in the prevalence of the drug-resistant Mycobacteria tuberculosis necessitates developing new types of anti-tuberculosis drugs. Here, we found that phloretin, a naturally-occurring flavonoid, has anti-mycobacterial effects on H37Rv, multi-drug-, and extensively drug-resistant clinical isolates, with minimum inhibitory concentrations of 182 and [...] Read more.

An increase in the prevalence of the drug-resistant Mycobacteria tuberculosis necessitates developing new types of anti-tuberculosis drugs. Here, we found that phloretin, a naturally-occurring flavonoid, has anti-mycobacterial effects on H37Rv, multi-drug-, and extensively drug-resistant clinical isolates, with minimum inhibitory concentrations of 182 and 364 μM, respectively. Since Mycobacteria cause lung inflammation that contributes to tuberculosis pathogenesis, anti-inflammatory effects of phloretin in interferon-γ-stimulated MRC-5 human lung fibroblasts and lipopolysaccharide (LPS)-stimulated dendritic cells were investigated. The release of interleukin (IL)-1β, IL-12, and tumor necrosis factor (TNF)-α was inhibited by phloretin. The mRNA levels of IL-1β, IL-6, IL-12, TNF-α, and matrix metalloproteinase-1, as well as p38 mitogen-activated protein kinase and extracellular signal-regulated kinase phosphorylation, were suppressed. A mouse in vivo study of LPS-stimulated lung inflammation showed that phloretin effectively suppressed the levels of TNF-α, IL-1β, and IL-6 in lung tissue with low cytotoxicity. Phloretin was found to bind M. tuberculosis β-ketoacyl acyl carrier protein synthase III (mtKASIII) with high affinity (7.221 × 10⁷ M⁻¹); a binding model showed hydrogen bonding of A-ring 2′-hydroxy and B-ring 4-hydroxy groups of phloretin with Asn261 and Cys122 of mtKASIII, implying that mtKASIII can be a potential target protein. Therefore, phloretin can be a useful dietary natural product with anti-tuberculosis benefits. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products)

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1665 KiB

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Improving Free Radical Scavenging Activity of Soy Isoflavone Glycosides Daidzin and Genistin by 3′-Hydroxylation Using Recombinant Escherichia coli

by Chien-Min Chiang, Dong-Sheng Wang and Te-Sheng Chang

Molecules 2016, 21(12), 1723; https://doi.org/10.3390/molecules21121723 - 15 Dec 2016

Cited by 22 | Viewed by 5145

Abstract

The present study describes the biotransformation of a commercially available crude extract of soy isoflavones, which contained significant amounts of the soy isoflavone glycosides daidzin and genistin, by recombinant Escherichia coli expressing tyrosinase from Bacillus megaterium. Two major products were isolated from [...] Read more.

The present study describes the biotransformation of a commercially available crude extract of soy isoflavones, which contained significant amounts of the soy isoflavone glycosides daidzin and genistin, by recombinant Escherichia coli expressing tyrosinase from Bacillus megaterium. Two major products were isolated from the biotransformation and identified as 3′-hydroxydaidzin and 3′-hydroxygenistin, respectively, based on their mass and nuclear magnetic resonance spectral data. The two 3′-hydroxyisoflavone glycosides showed potent 2,2-diphenyl-1-picrylhydrazyl free radical scavenging activity with IC₅₀ values of 7.4 and 9.8 μM for 3′-hydroxydaidzin and 3′-hydroxygenistin, respectively. The free radical scavenging activities of the two 3′-hydroxyisoflavone glycosides were, respectively, 120 and 72 times higher than the activity of their precursors, daidzin and genistin, and were also stronger than the activity of ascorbic acid, which showed an IC₅₀ value of 15.1 μM. This is the first report of the bio-production and potential antioxidant applications of both 3′-hydroxydaidzin and 3′-hydroxygenistin. Full article

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Polyphenols Isolated from Xanthoceras sorbifolia Husks and Their Anti-Tumor and Radical-Scavenging Activities

by Chun-Yan Yang, Wei Ha, Yong Lin, Kan Jiang, Jun-Li Yang and Yan-Ping Shi

Molecules 2016, 21(12), 1694; https://doi.org/10.3390/molecules21121694 - 09 Dec 2016

Cited by 27 | Viewed by 5188

Abstract

Xanthoceras sorbifolia Bunge. is used in traditional medicine in North China. To evaluate the anti-tumor and radical-scavenging activities of X. sorbifolia husks polyphenols and determine their structure-activity relationships, 37 polyphenols 1–37 were obtained by bioassay-guided fractionation. Two new compounds 1– [...] Read more.

Xanthoceras sorbifolia Bunge. is used in traditional medicine in North China. To evaluate the anti-tumor and radical-scavenging activities of X. sorbifolia husks polyphenols and determine their structure-activity relationships, 37 polyphenols 1–37 were obtained by bioassay-guided fractionation. Two new compounds 1–2, and compounds 5, 6, 8, 9, 11, 14–17, 21–25, 27–29, 31, 33, 34, 36, and 37 were isolated from the genus Xanthoceras for the first time. Compounds 1–37 did not show strong cytotoxicity against the four tested tumor cell lines (A549, HepG2, MGC-803, and MFC) compared to paclitaxel and under the conditions tested in the anti-tumor assay, but compounds 3, 4, 7, 8, 10, 18–20, 25, 26, 29, 30, 32, and 35 exhibited stronger radical-scavenging activity than ascorbic acid in a 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt assay. This was the first report on the anti-tumor and radical-scavenging activities of the polyphenols isolated from X. sorbifolia husks. Overall, the present study contributed valuable information concerning X. sorbifolia husks use in medicine and pharmacology. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products)

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1929 KiB

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Glycyrrhizic Acid Reduces Heart Rate and Blood Pressure by a Dual Mechanism

by Kailash Singh, Aung Moe Zaw, Revathi Sekar, Ahuja Palak, Ahmed A. Allam, Jamaan Ajarem and Billy K. C. Chow

Molecules 2016, 21(10), 1291; https://doi.org/10.3390/molecules21101291 - 27 Sep 2016

Cited by 14 | Viewed by 5603

Abstract

Beta adrenergic receptors are crucial for their role in rhythmic contraction of heart along with their role in the pathological conditions such as tachycardia and high risk of heart failure. Studies report that the levels of beta-1 adrenergic receptor tend to decrease by [...] Read more.

Beta adrenergic receptors are crucial for their role in rhythmic contraction of heart along with their role in the pathological conditions such as tachycardia and high risk of heart failure. Studies report that the levels of beta-1 adrenergic receptor tend to decrease by 50%, whereas, the levels of beta-2 adrenergic receptor remains constant during the risk of heart failure. Beta blockers—the antagonistic molecules for beta-adrenergic receptors, function by slowing the heart rate, which thereby allows the left ventricle to fill completely during tachycardia incidents and hence helps in blood pumping capacity of heart and reducing the risk of heart failure. In the present study, we investigate the potential of glycyrrhizic acid (GA) as a possible principal drug molecule for cardiac arrhythmias owing to its ability to induce reduction in the heart rate and blood pressure. We use in vitro and in silico approach to study GA′s effect on beta adrenergic receptor along with an in vivo study to examine its effect on heart rate and blood pressure. Additionally, we explore GA′s proficiency in eliciting an increase in the plasma levels of vasoactive intestinal peptide, which by dilating the blood vessel consequently, can be a crucial aid during the occurrence of a potential heart attack. Therefore, we propose GA as a potential principal drug molecule via its potential in modulating heart rate and blood pressure. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products)

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The Changes in Color, Soluble Sugars, Organic Acids, Anthocyanins and Aroma Components in “Starkrimson” during the Ripening Period in China

by Yulian Liu, Nianlai Chen, Zonghuan Ma, Fei Che, Juan Mao and Baihong Chen

Molecules 2016, 21(6), 812; https://doi.org/10.3390/molecules21060812 - 22 Jun 2016

Cited by 22 | Viewed by 5641

Abstract

“Starkrimson” is a traditional apple cultivar that was developed a long time ago and was widely cultivated in the arid region of the northern Wei River of China. However, little information regarding the quality characteristics of “Starkrimson” fruit has been reported in this [...] Read more.

“Starkrimson” is a traditional apple cultivar that was developed a long time ago and was widely cultivated in the arid region of the northern Wei River of China. However, little information regarding the quality characteristics of “Starkrimson” fruit has been reported in this area. To elucidate these characteristics, the color, soluble sugars, organic acids, anthocyanins and aroma components were measured during the ripening period through the use of high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). The results indicated that the changes in anthocyanin contents took place later than the changes in the Commission International Eclairage (CIE) parameters. Meanwhile, cyanidin 3-galactoside (cy3-gal), fructose, sucrose, glucose and malic acid were the primary organic compounds, and 1-butanol-2-methyl-acetate, 2-hexenal and 1-hexanol were the most abundant aroma components in the skin. Furthermore, rapidly changing soluble sugars and organic acid synchronization took place in the early ripening period, while rapidly changing aroma components occurred later, on the basis of fresh weight. This result suggested that the production of aroma components might be a useful index of apple maturity. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products)

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