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Structure-Activity Relationship of Natural Products 2018

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (30 May 2018) | Viewed by 78044

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Special Issue Editor

Prof. Dr. Antonio Evidente

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Guest Editor

1. Department of Chemical Sciences, University of Naples “Federico II”, Complesso Universitario Monte S. Angelo, Via Cintia 4, 80126 Napoli, Italy
2. Institute of Sciences of Food Production, National Research Council, Via Amendola 122/O, 70125 Bari, Italy
Interests: Fungi; Bacterial; plant; metabolites; chemistry; spectroscopy; stereochemistry; biological activity; structure-activity relationships
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Special Issue Information

Dear Colleagues,

Microbial, plant and terrestrial and marine organisms hold a great deal of promise in biosynthesizing secondary metabolites. These metabolites belong to all the different classes of natural compounds, such as terpenes, phenylpropanoids, polyketides, alkaloids, etc. Thus, these organisms represent a very good source of natural substances, frequently possessing very interesting biological activities with potential applications in different fields. Their practical applications sometimes require an increase in their stability, selectivity, solubility in water, or the best suitable formulation. Studies carried out on the relationship between the chemical structure of a natural compound and its biological activities is an important starting point to obtain information on structural features that are essential for biological activity. Furthermore, the same studies give the necessary information to reach the aims mentioned above for their practical application. All researchers working in the field, are cordially invited to contribute original research papers or reviews to this Special Issue of Molecules, which reports on the structure–activity relationship studies of natural products with different biological activities.

Prof. Dr. Antonio Evidente
Guest Editor

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Keywords

natural products
source and chemical characterization
biological activities
chemical modification
structure activity relationships (SAR)

Published Papers (12 papers)

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Research

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23 pages, 5734 KiB

Open AccessArticle

Identification of Natural Compounds against Neurodegenerative Diseases Using In Silico Techniques

by Larisa Ivanova, Mati Karelson and Dimitar A. Dobchev

Molecules 2018, 23(8), 1847; https://doi.org/10.3390/molecules23081847 - 25 Jul 2018

Cited by 15 | Viewed by 3988

Abstract

The aim of this study was to identify new potentially active compounds for three protein targets, tropomyosin receptor kinase A (TrkA), N-methyl-d-aspartate (NMDA) receptor, and leucine-rich repeat kinase 2 (LRRK2), that are related to various neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and neuropathic pain. We used a combination of machine learning methods including artificial neural networks and advanced multilinear techniques to develop quantitative structure–activity relationship (QSAR) models for all target proteins. The models were applied to screen more than 13,000 natural compounds from a public database to identify active molecules. The best candidate compounds were further confirmed by docking analysis and molecular dynamics simulations using the crystal structures of the proteins. Several compounds with novel scaffolds were predicted that could be used as the basis for development of novel drug inhibitors related to each target. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products 2018)

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12 pages, 811 KiB

Open AccessFeature PaperArticle

(+)-epi-Epoformin, a Phytotoxic Fungal Cyclohexenepoxide: Structure Activity Relationships

by Antonio Cala, Marco Masi, Alessio Cimmino, José M. G. Molinillo, Francisco A. Macias and Antonio Evidente

Molecules 2018, 23(7), 1529; https://doi.org/10.3390/molecules23071529 - 25 Jun 2018

Cited by 14 | Viewed by 3380

Abstract

(+)-epi-Epoformin (1), is a fungal cyclohexene epoxide isolated together with diplopimarane and sphaeropsidins A and C, a nor-ent-pimarane and two pimaranes, from the culture filtrates of Diplodia quercivora, a fungal pathogen for cork oak in Sardinia, Italy. Compound 1 possesses a plethora of biological activities, including antifungal, zootoxic and phytotoxic activity. The last activity and the peculiar structural feature of 1 suggested to carry out a structure activity relationship study, preparing eight key hemisynthetic derivatives and the phytotoxicity was assayed. The complete spectroscopic characterization and the activity in the etiolated wheat coleoptile bioassay of all the compounds is reported. Most of the compounds inhibited growth and some of them had comparable or higher activity than the natural product and the reference herbicide Logran. As regards the structure-activity relationship, the carbonyl proved to be essential for their activity of 1, as well as the conjugated double bond, while the epoxide could be altered with no significant loss. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products 2018)

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14 pages, 1356 KiB

Open AccessFeature PaperArticle

Natural Aromatic Compounds as Scaffolds to Develop Selective G-Quadruplex Ligands: From Previously Reported Berberine Derivatives to New Palmatine Analogues

by Marco Franceschin, Lorenzo Cianni, Massimo Pitorri, Emanuela Micheli, Stefano Cacchione, Claudio Frezza, Mauro Serafini, Ming-Hao Hu, Huafi Su, Zhishu Huang, Lianquan Gu and Armandodoriano Bianco

Molecules 2018, 23(6), 1423; https://doi.org/10.3390/molecules23061423 - 12 Jun 2018

Cited by 18 | Viewed by 5318

Abstract

In this paper, the selective interactions of synthetic derivatives of two natural compounds, berberine and palmatine, with DNA G-quadruplex structures were reported. In particular, the previous works on this subject concerning berberine were further presented and discussed, whereas the results concerning palmatine are presented here for the first time. In detail, these palmatine derivatives were developed by inserting seven different small peptide basic chains, giving several new compounds that have never been reported before. The preliminary studies of the interactions of these compounds with various G-quadruplex-forming sequences were carried out by means of various structural and biochemical techniques, which showed that the presence of suitable side chains is very useful for improving the interaction of the ligands with G-quadruplex structures. Thus, these new palmatine derivatives might act as potential anticancer drugs. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products 2018)

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8 pages, 1883 KiB

Open AccessArticle

Synthesis and Promotion of the Osteoblast Proliferation Effect of Morroniside Derivatives

by Hua Han, ZhengQing Li, Na Qu, Si Chen and PeiLiang Dong

Molecules 2018, 23(6), 1412; https://doi.org/10.3390/molecules23061412 - 11 Jun 2018

Cited by 4 | Viewed by 3224

Abstract

Sambucus williamsii Hance has been used in fractures for thousands of years, but research on its active components, such as morroniside, until now had not been carried out. In this study, morroniside was taken as the leading compound, and fourteen derivatives were synthesized. The promotion of osteoblast proliferation effect of the derivatives was evaluated on MC3T3-E1 cells. Five derivatives (2, 3, 4, 5, and 14) showed a good proliferation effect on MC3T3-E1 cells, and their promoted expression effects on OC (Osteocalcin) and ALP (Alkaline phosphatase) in MC3T3-E1 cells were measured. Compound 3 was shown to have the strongest proliferation effect (EC₅₀ = 14.78 ± 1.17 μg/mL) and to significantly promote the expression of OC and ALP. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products 2018)

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11 pages, 2426 KiB

Open AccessArticle

Structure–Activity Relationship and Molecular Docking of Natural Product Library Reveal Chrysin as a Novel Dipeptidyl Peptidase-4 (DPP-4) Inhibitor: An Integrated In Silico and In Vitro Study

by Poonam Kalhotra, Veera C. S. R. Chittepu, Guillermo Osorio-Revilla and Tzayhri Gallardo-Velázquez

Molecules 2018, 23(6), 1368; https://doi.org/10.3390/molecules23061368 - 06 Jun 2018

Cited by 48 | Viewed by 9031

Abstract

Numerous studies indicate that diets with a variety of fruits and vegetables decrease the incidence of severe diseases, like diabetes, obesity, and cancer. Diets contain a variety of bioactive compounds, and their features, like diverge scaffolds, and structural complexity make them the most successful source of potential leads or hits in the process of drug discovery and drug development. Recently, novel serine protease dipeptidyl peptidase-4 (DPP-4) inhibitors played a role in the management of diabetes, obesity, and cancer. This study describes the development of field template, field-based qualitative structure–activity relationship (SAR) model demonstrating DPP-4 inhibitors of natural origin, and the same model is used to screen virtually focused food database composed of polyphenols as potential DPP-4 inhibitors. Compounds’ similarity to field template, and novelty score “high and very high”, were used as primary criteria to identify novel DPP-4 inhibitors. Molecular docking simulations were performed on the resulting natural compounds using FlexX algorithm. Finally, one natural compound, chrysin, was chosen to be evaluated experimentally to demonstrate the applicability of constructed SAR model. This study provides the molecular insights necessary in the discovery of new leads as DPP-4 inhibitors, to improve the potency of existing DPP-4 natural inhibitors. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products 2018)

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17 pages, 785 KiB

Open AccessArticle

Evaluating Molecular Properties Involved in Transport of Small Molecules in Stratum Corneum: A Quantitative Structure-Activity Relationship for Skin Permeability

by Chen-Peng Chen, Chan-Cheng Chen, Chia-Wen Huang and Yen-Ching Chang

Molecules 2018, 23(4), 911; https://doi.org/10.3390/molecules23040911 - 15 Apr 2018

Cited by 53 | Viewed by 8896

Abstract

The skin permeability (Kp) defines the rate of a chemical penetrating across the stratum corneum. This value is widely used to quantitatively describe the transport of molecules in the outermost layer of epidermal skin and indicate the significance of skin absorption. This study defined a Kp quantitative structure-activity relationship (QSAR) based on 106 chemical substances of Kp measured using human skin and interpreted the molecular interactions underlying transport behavior of small molecules in the stratum corneum. The Kp QSAR developed in this study identified four molecular descriptors that described the molecular cyclicity in the molecule reflecting local geometrical environments, topological distances between pairs of oxygen and chlorine atoms, lipophilicity, and similarity to antineoplastics in molecular properties. This Kp QSAR considered the octanol-water partition coefficient to be a direct influence on transdermal movement of molecules. Moreover, the Kp QSAR identified a sub-domain of molecular properties initially defined to describe the antineoplastic resemblance of a compound as a significant factor in affecting transdermal permeation of solutes. This finding suggests that the influence of molecular size on the chemical’s skin-permeating capability should be interpreted with other relevant physicochemical properties rather than being represented by molecular weight alone. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products 2018)

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10 pages, 909 KiB

Open AccessArticle

Identification of Bichalcones as Sirtuin Inhibitors by Virtual Screening and In Vitro Testing

by Berin Karaman, Zayan Alhalabi, Sören Swyter, Shetonde O. Mihigo, Kerstin Andrae-Marobela, Manfred Jung, Wolfgang Sippl and Fidele Ntie-Kang

Molecules 2018, 23(2), 416; https://doi.org/10.3390/molecules23020416 - 14 Feb 2018

Cited by 22 | Viewed by 4926

Abstract

Sirtuins are nicotinamide adenine dinucleotide (NAD⁺)-dependent class III histone deacetylases, which have been linked to the pathogenesis of numerous diseases, including HIV, metabolic disorders, neurodegeneration and cancer. Docking of the virtual pan-African natural products library (p-ANAPL), followed by in vitro testing, resulted in the identification of two inhibitors of sirtuin 1, 2 and 3 (sirt1–3). Two bichalcones, known as rhuschalcone IV (8) and an analogue of rhuschalcone I (9), previously isolated from the medicinal plant Rhus pyroides, were shown to be active in the in vitro assay. The rhuschalcone I analogue (9) showed the best activity against sirt1, with an IC₅₀ value of 40.8 µM. Based on the docking experiments, suggestions for improving the biological activities of the newly identified hit compounds have been provided. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products 2018)

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8 pages, 795 KiB

Open AccessCommunication

Novel Topologically Complex Scaffold Derived from Alkaloid Haemanthamine

by Karthik Govindaraju, Marco Masi, Margaux Colin, Veronique Mathieu, Antonio Evidente, Todd W. Hudnall and Alexander Kornienko

Molecules 2018, 23(2), 255; https://doi.org/10.3390/molecules23020255 - 28 Jan 2018

Cited by 12 | Viewed by 4053

Abstract

The generation of natural product-like compound collections has become an important area of research due to low hit rates found with synthetic high-throughput libraries. One method of generating compounds occupying the areas of chemical space not accessible to synthetic planar heterocyclic structures is the utilization of natural products as starting materials. In the current work, using a ring-closing iodoalkoxylation reaction, alkaloid haemanthamine was transformed into a unique structural framework possessing an intricate ring system and a large number of stereocenters. The structure of the new compound was confirmed with an X-ray analysis. A small number of derivatives of this new compound were synthesized as a demonstration of the possibility of generating a large natural product-like compound collection based on the new structural framework. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products 2018)

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11 pages, 1767 KiB

Open AccessArticle

Antioxidant and Cytoprotective Effects of the Di-O-Caffeoylquinic Acid Family: The Mechanism, Structure–Activity Relationship, and Conformational Effect

by Xican Li, Ke Li, Hong Xie, Yulu Xie, Yueying Li, Xiaojun Zhao, Xiaohua Jiang and Dongfeng Chen

Molecules 2018, 23(1), 222; https://doi.org/10.3390/molecules23010222 - 20 Jan 2018

Cited by 53 | Viewed by 4830

Abstract

In this study, a series of di-O-caffeoylquinic acids (di-COQs) were systematically investigated for their antioxidant and cytoprotective effects towards •OH-damaged bone marrow-derived mesenchymal stem cells (bmMSCs). Five di-COQs were measured using a set of antioxidant assays. The results show that adjacent 4,5-Di-O-caffeoylquinic acid (4,5-COQ) and 3,4-di-O-caffeoylquinic acid (3,4-COQ) always gave lower IC₅₀ values than did non-adjacent di-COQs. In the Fe²⁺-chelating assay, 4,5-COQ and 3,4-COQ presented greater UV-Vis spectra and darker colors than did non-adjacent di-COQs. In the UPLC-ESI-MS/MS analysis, no corresponding radical adduct formation (RAF) peak was found in the reaction products of di-COQs with PTIO•. In the MTT assay, all di-COQs (especially 1,5-COQ, 1,3-COQ, and 4,5-COQ) dose-dependently increased the cellular viabilities of •OH-damaged bmMSCs. Based on this evidence, we conclude that the five antioxidant di-COQs can protect bmMSCs from •OH-induced damage. Their antioxidant mechanisms may include electron-transfer (ET), H⁺-transfer, and Fe²⁺-chelating, except for RAF. Two adjacent di-COQs (4,5-COQ and 3,4-COQ) always possessed a higher antioxidant ability than the non-adjacent di-COQs (1,3-COQ, 1,5-COQ, and 3,5-COQ) in chemical models. However, non-adjacent 1,3-COQ and 1,5-COQ exhibited a higher cytoprotective effect than did adjacent di-COQs. These differences can be attributed to the relative positions of two caffeoyl moieties and, ultimately, to the conformational effect from the cyclohexane skeleton. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products 2018)

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Review

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17 pages, 3800 KiB

Open AccessFeature PaperReview

Structure-Activity Relationship of Cannabis Derived Compounds for the Treatment of Neuronal Activity-Related Diseases

by Cristina Prandi, Marco Blangetti, Dvora Namdar and Hinanit Koltai

Molecules 2018, 23(7), 1526; https://doi.org/10.3390/molecules23071526 - 25 Jun 2018

Cited by 31 | Viewed by 12263

Abstract

Cannabis sativa active compounds are extensively studied for their therapeutic effects, beyond the well-known psychotropic activity. C. Sativa is used to treat different medical indications, such as multiple sclerosis, spasticity, epilepsy, ulcerative colitis and pain. Simultaneously, basic research is discovering new constituents of cannabis-derived compounds and their receptors capable of neuroprotection and neuronal activity modulation. The function of the various phytochemicals in different therapeutic processes is not fully understood, but their significant role is starting to emerge and be appreciated. In this review, we will consider the structure-activity relationship (SAR) of cannabinoid compounds able to bind to cannabinoid receptors and act as therapeutic agents in neuronal diseases, e.g., Parkinson’s disease. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products 2018)

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44 pages, 3097 KiB

Open AccessFeature PaperReview

Structure-Dependent Activity of Natural GABA(A) Receptor Modulators

by Serhat Sezai Çiçek

Molecules 2018, 23(7), 1512; https://doi.org/10.3390/molecules23071512 - 22 Jun 2018

Cited by 26 | Viewed by 10616

Abstract

GABA(A) receptors are ligand-gated ion channels consisting of five subunits from eight subfamilies, each assembled in four hydrophobic transmembrane domains. This pentameric structure not only allows different receptor binding sites, but also various types of ligands, such as orthosteric agonists and antagonists, positive and negative allosteric modulators, as well as second-order modulators and non-competitive channel blockers. A fact, that is also displayed by the variety of chemical structures found for both, synthetic as well as nature-derived GABA(A)-receptor modulators. This review covers the literature for natural GABA(A)-receptor modulators until the end of 2017 and discusses their structure-activity relationship. Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products 2018)

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30 pages, 3961 KiB

Open AccessReview

Fungal Metabolites Antagonists towards Plant Pests and Human Pathogens: Structure-Activity Relationship Studies

by Marco Masi, Paola Nocera, Pierluigi Reveglia, Alessio Cimmino and Antonio Evidente

Molecules 2018, 23(4), 834; https://doi.org/10.3390/molecules23040834 - 05 Apr 2018

Cited by 27 | Viewed by 6103

Abstract

Fungi are able to produce many bioactive secondary metabolites that belong to different classes of natural compounds. Some of these compounds have been selected for their antagonism against pests and human pathogens and structure–activity relationship (SAR) studies have been performed to better understand which structural features are essential for the biological activity. In some cases, these studies allowed for the obtaining of hemisynthetic derivatives with increased selectivity and stability in respect to the natural products as well as reduced toxicity in view of their potential practical applications. This review deals with the SAR studies performed on fungal metabolites with potential fungicidal, bactericidal, insecticidal, and herbicidal activities from 1990 to the present (beginning of 2018). Full article

(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products 2018)

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