Chemical Space and Biological Target Network of Anti-Inflammatory Natural Products

Natural Products (NPs) are molecular' special equipment ' that impart survival benefits on their producers in nature. Due to their evolved functions to modulate biology these privileged metabolites are substantially represented in the drug market and are continuing to contribute to the discovery of innovative medicines such as the recently approved semi-synthetic derivative of the bacterial alkaloid staurosporin in oncology indications. The innovation of low molecular weight compounds in modern drug discovery is built on rapid progress in chemical, molecular biological, pharmacological and data sciences, which together provide a rich understanding of disease-driving molecular interactions and how to modulate them. NPs investigated in these pharmaceutical research areas create new perspectives on their chemical and biological features and thereby new chances to advance medical research. New methods in analytical chemistry linked with searchable NP-databases solved the issue of reisolation and enabled targeted and efficient access to novel molecules from nature. Cheminformatics delivers high resolution descriptions of NPs and explores the substructures that systematically map NP-chemical space by sp3-enriched fragments. Whole genome sequencing has revealed the existence of collocated gene clusters that form larger functional entities together with proximate resistance factors thus avoiding self-inhibition of the encoded metabolites. The analysis of bacterial and fungal genes provides tantalizing glimpses of new compound-target pairs of therapeutic value. Furthermore, a dedicated investigation of structurally unique, selectively active NPs in chemical biology demonstrates their extraordinary power as shuttles between new biological target spaces of pharmaceutical relevance.

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Anti-inflammatory and anti-tubercular properties screening of natural products from Plectranthus species

10.1055/s-0037-1608136 ◽

2017 ◽

Author(s):

J Marçalo ◽

C Garcia ◽

L Custódio ◽

M Nicolai ◽

C Reis ◽

...

Keyword(s):

Natural Products ◽

Anti Inflammatory

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Anti-Inflammatory Properties of Plant Derived Natural Products – A Systematic Review

Current Medicinal Chemistry ◽

10.2174/0929867325666190523123357 ◽

2019 ◽

Vol 26 (24) ◽

pp. 4506-4536 ◽

Cited By ~ 4

Author(s):

Iris E. Allijn ◽

René P. Brinkhuis ◽

Gert Storm ◽

Raymond M. Schiffelers

Keyword(s):

Systematic Review ◽

Natural Products ◽

Positive Control ◽

Therapeutic Effects ◽

Reference Compound ◽

Individual Molecular Species ◽

The Past ◽

Anti Inflammatory ◽

The Individual ◽

Natural Medicines

Traditionally, natural medicines have been administered as plant extracts, which are composed of a mixture of molecules. The individual molecular species in this mixture may or may not contribute to the overall medicinal effects and some may even oppose the beneficial activity of others. To better control therapeutic effects, studies that characterized specific molecules and describe their individual activity that have been performed over the past decades. These studies appear to underline that natural products are particularly effective as antioxidants and anti-inflammatory agents. In this systematic review we aimed to identify potent anti-inflammatory natural products and relate their efficacy to their chemical structure and physicochemical properties. To identify these compounds, we performed a comprehensive literature search to find those studies, in which a dose-response description and a positive control reference compound was used to benchmark the observed activity. Of the analyzed papers, 7% of initially selected studies met these requirements and were subjected to further analysis. This analysis revealed that most selected natural products indeed appeared to possess anti-inflammatory activities, in particular anti-oxidative properties. In addition, 14% of the natural products outperformed the remaining natural products in all tested assays and are attractive candidates as new anti-inflammatory agents.

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Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

Current Medicinal Chemistry ◽

10.2174/0929867327666200730213215 ◽

2020 ◽

Vol 27 ◽

Author(s):

Reyaz Hassan Mir ◽

Abdul Jalil Shah ◽

Roohi Mohi-ud-din ◽

Faheem Hyder Potoo ◽

Mohd. Akbar Dar ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Natural Products ◽

Protective Action ◽

New Drugs ◽

Huperzine A ◽

Brain Disorder ◽

Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

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Chemical Elicitors Induce Rare Bioactive Secondary Metabolites in Deep-Sea Bacteria under Laboratory Conditions

Metabolites ◽

10.3390/metabo11020107 ◽

2021 ◽

Vol 11 (2) ◽

pp. 107

Author(s):

Rafael de Felício ◽

Patricia Ballone ◽

Cristina Freitas Bazzano ◽

Luiz F. G. Alves ◽

Renata Sigrist ◽

...

Keyword(s):

Natural Products ◽

Secondary Metabolites ◽

Natural Product ◽

Deep Sea ◽

Chemical Space ◽

Bacterial Genome ◽

Vast Number ◽

Bacterial Metabolites ◽

Laboratory Conditions ◽

Deep Sea Bacteria

Bacterial genome sequencing has revealed a vast number of novel biosynthetic gene clusters (BGC) with potential to produce bioactive natural products. However, the biosynthesis of secondary metabolites by bacteria is often silenced under laboratory conditions, limiting the controlled expression of natural products. Here we describe an integrated methodology for the construction and screening of an elicited and pre-fractionated library of marine bacteria. In this pilot study, chemical elicitors were evaluated to mimic the natural environment and to induce the expression of cryptic BGCs in deep-sea bacteria. By integrating high-resolution untargeted metabolomics with cheminformatics analyses, it was possible to visualize, mine, identify and map the chemical and biological space of the elicited bacterial metabolites. The results show that elicited bacterial metabolites correspond to ~45% of the compounds produced under laboratory conditions. In addition, the elicited chemical space is novel (~70% of the elicited compounds) or concentrated in the chemical space of drugs. Fractionation of the crude extracts further evidenced minor compounds (~90% of the collection) and the detection of biological activity. This pilot work pinpoints strategies for constructing and evaluating chemically diverse bacterial natural product libraries towards the identification of novel bacterial metabolites in natural product-based drug discovery pipelines.

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Thiophene-Based Compounds with Potential Anti-Inflammatory Activity

Pharmaceuticals ◽

10.3390/ph14070692 ◽

2021 ◽

Vol 14 (7) ◽

pp. 692

Author(s):

Ryldene Marques Duarte da Cruz ◽

Francisco Jaime Bezerra Mendonça-Junior ◽

Natália Barbosa de Mélo ◽

Luciana Scotti ◽

Rodrigo Santos Aquino de Araújo ◽

...

Keyword(s):

Inflammatory Diseases ◽

Structural Characteristics ◽

Tiaprofenic Acid ◽

Inflammatory Activity ◽

Drug Candidates ◽

Biological Target ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

Privileged Structures

Rheumatoid arthritis, arthrosis and gout, among other chronic inflammatory diseases are public health problems and represent major therapeutic challenges. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed clinical treatments, despite their severe side effects and their exclusive action in improving symptoms, without effectively promoting the cure. However, recent advances in the fields of pharmacology, medicinal chemistry, and chemoinformatics have provided valuable information and opportunities for development of new anti-inflammatory drug candidates. For drug design and discovery, thiophene derivatives are privileged structures. Thiophene-based compounds, like the commercial drugs Tinoridine and Tiaprofenic acid, are known for their anti-inflammatory properties. The present review provides an update on the role of thiophene-based derivatives in inflammation. Studies on mechanisms of action, interactions with receptors (especially against cyclooxygenase (COX) and lipoxygenase (LOX)), and structure-activity relationships are also presented and discussed. The results demonstrate the importance of thiophene-based compounds as privileged structures for the design and discovery of novel anti-inflammatory agents. The studies reveal important structural characteristics. The presence of carboxylic acids, esters, amines, and amides, as well as methyl and methoxy groups, has been frequently described, and highlights the importance of these groups for anti-inflammatory activity and biological target recognition, especially for inhibition of COX and LOX enzymes.

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MeFSAT: a curated natural product database specific to secondary metabolites of medicinal fungi

RSC Advances ◽

10.1039/d0ra10322e ◽

2021 ◽

Vol 11 (5) ◽

pp. 2596-2607

Author(s):

R. P. Vivek-Ananth ◽

Ajaya Kumar Sahoo ◽

Kavyaa Kumaravel ◽

Karthikeyan Mohanraj ◽

Areejit Samal

Keyword(s):

Natural Products ◽

Secondary Metabolites ◽

Natural Product ◽

Chemical Space ◽

Therapeutic Uses ◽

Medicinal Fungi ◽

Fungal Natural Products

First dedicated manually curated resource on secondary metabolites and therapeutic uses of medicinal fungi. Cheminformatics based analysis of the chemical space of fungal natural products.

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Synthetic Strategies to Access Heteroatomic Spirocentres Embedded in Natural Products

Synthesis ◽

10.1055/a-1379-2312 ◽

2021 ◽

Author(s):

Michael P. Badart ◽

Bill C. Hawkins

Keyword(s):

Natural Products ◽

Heterocyclic Compound ◽

Chemical Space ◽

Three Dimensional ◽

Coupling Reactions ◽

Conjugate Additions ◽

Biological Targets ◽

Compound Libraries ◽

The Common ◽

Significant Attention

AbstractThe spirocyclic motif is abundant in natural products and provides an ideal three-dimensional template to interact with biological targets. With significant attention historically expended on the synthesis of flat-heterocyclic compound libraries, methods to access the less-explored three-dimensional medicinal-chemical space will continue to increase in demand. Herein, we highlight by reaction class the common strategies used to construct the spirocyclic centres embedded in a series of well-studied natural products.1 Introduction2 Cycloadditions3 Palladium-Catalysed Coupling Reactions4 Conjugate Additions5 Imines, Aminals, and Hemiaminal Ethers6 Mannich-Type Reactions7 Oxidative Dearomatisation8 Alkylation9 Organometallic Additions10 Conclusions

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Natural product fragment combination to performance-diverse pseudo-natural products

Nature Communications ◽

10.1038/s41467-021-22174-4 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 2

Author(s):

Michael Grigalunas ◽

Annina Burhop ◽

Sarah Zinken ◽

Axel Pahl ◽

José-Manuel Gally ◽

...

Keyword(s):

Natural Products ◽

Product Design ◽

Natural Product ◽

Chemical Space ◽

Biological Evaluation ◽

Product Structure ◽

Biologically Relevant ◽

Biologically Relevant Chemical Space

AbstractNatural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space.

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