Biochemometrics has emerged as promising strategy for the targeted identification of bioactive constituents from natural sources. It is based on the correlation of bioactivity data with chemical data to reveal constituents contributing to activity. Providing complementary data and structural information, MS- and NMR-based biochemometric approaches have both been separately applied in the past. The herein presented study is dedicated to the evaluation of a combined MS- and NMR-based biochemometric workflow for the unambiguous identification of bioactives. As an example, a flower extract of Maxim. was selected to unravel bioactive constituents in the context of dry eye disease pathology. While NMR-based biochemometrics relies on heterocovariance analysis (HetCA) of H NMR spectra using the previously established ELINA approach, a biochemometric molecular network was generated for the MS-based approach. Both analyses were performed in parallel and were ultimately combined to increase their power to identify the bioactive constituents from the complex mixture. As a result, phenylethanoid glycosides and triterpene saponins were discovered as main contributors for the antioxidant and cytotoxic effects of the extract. This article illustrates the advantages, opportunities, and limitations of MS and NMR in the context of biochemometrics.

A chemical investigation of the coral-derived fungus sp. TJ403-AL05 led to the isolation of 18 duclauxin analogues (-), 14 of which, taladuxins A-N (-), are new and consist of the first example of duclauxin fused with one 1,6-dioxaspiro[4.5]decan-2-one moiety (), as well as its biosynthetic product (), and 12 6/6/6/5/6/6/6 heptacyclic derivatives (-). Comprehensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, DP4+ probability analyses, single-crystal X-ray diffraction, and vibrational circular dichroism (VCD) calculations were employed to characterize their structures and revise the published structure of verruculosin B. An efficient H NMR method was established to discriminate 1 and 1 configurations at C-1 of 6/6/6/5/6/6/6 heptacyclic duclauxins according to chemical shift differences of diastereotopic methylene H-11 or H-12 (Δδ or Δδ). Compounds , -, -, and exhibited moderate inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPPD), with IC values ranging from 17.1 to 71.3 μM.

In this work, we describe the results of a computational investigation aimed at identifying potential biological targets of honokiol, magnolol and a series of synthetic prodrug derivatives obtained through esterification of the free hydroxyl groups. The ligand-based and structure-based analyses revealed that these compounds potentially interact with several biological targets, some of which are known while others are new. Honokiol, magnolol, and three of the newly synthesized derivatives may bind to estrogen receptors ERα and ERβ. Biological testing confirmed that these compounds modulate estrogen-regulated transcriptional activity mediated by ERα or ERβ with potencies in the nanomolar range. In particular, magnolol and one of its derivatives () behaved as partial antagonists of ERα and ERβ, while compounds and behaved as partial agonists. These findings validate the computational predictions and shed light on the mechanism of action of these natural compounds, paving the way for further investigation in the context of targeted therapies.

Phytochemical investigations of the twig and leaf extracts of resulted in the isolation and identification of two new alkaloids, goniotortiline () and goniotortilactam (), three new styryl lactone derivatives, goniotortilactone () and goniotortilols A () and B (), and 25 known compounds. Their structures were elucidated by spectroscopic methods and HRESITOFMS data. Compounds , , , , , and inhibited nitric oxide (NO) production with IC values ranging from 8.7 ± 0.1 to 17 ± 1 μM, revealing stronger effects than the standard drug, dexamethasone (IC 16.9 ± 2.2 μM), and compound possessed the most potent NO production inhibition. Compounds and demonstrated notable efficacy in enhancing glucose consumption with IC values of 77 ± 4 and 66 ± 4 μM, respectively, while their glucose uptakes were 1.7- and 2-fold, respectively.

Natural products are a sustainable resource for drug discovery, but their identification in complex mixtures remains a daunting task. We present an automated pipeline that compares, harmonizes and ranks the annotations of LC-HRMS data by different tools. When applied to 7,400 extracts derived from 6,566 strains belonging to 86 actinomycete genera, it yielded 150,000 molecules after processing over 50 million MS features. The web-based Molecules Gateway provides a highly interactive access to experimental and calculated data for these molecules, along with the metadata related to extracts and producer strains. We show how the Molecules Gateway can be used to rapidly identify known hard to find microbial products, unreported analogs of known families and not yet described metabolites. The Molecules Gateway, which complements available repositories, contains annotated MS data, both acquired and computationally processed under an identical workflow, making it suitable for global analyses which reveal a large and untapped chemical diversity afforded by actinomycetes.

Danshensu extracted with traditional Chinese medicine has a wide range of bioactivities. Danshensu containing a catechol moiety has a moderate inhibitory effect on SARS-CoV-2 3CL (IC = 2.2 μM) by a reversible covalent interaction and exhibits good anti-inflammatory activity. To enhance the inhibitory activity, we introduced Michael receptors into the side chain of danshensu as a possible covalent warhead and blocked the covalent binding sites of catechol moiety to yield chalcone derivatives. The resulting chalcone derivatives, and , were found to inhibit SARS-CoV-2 3CL with IC values of 83.2 and 261.3 nM, respectively. Furthermore, and inhibit viral replication in the SARS-CoV-2 replicon system with EC values of 19.9 and 11.7 μM, respectively. Time-dependent inhibition experiment and mass spectrometry show that acted as a noncovalent mixed inhibitor, while likely binds covalently at Cys145. The interaction mechanism between SARS-CoV-2 3CL and or was characterized by molecular docking studies. Additionally, both and demonstrated potent anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. These promising results suggest that chalcone derivatives and can serve as bifunctional molecules with both antivirus and anti-inflammatory properties.

We have achieved the divergent total synthesis of nine isoflavone natural products - starting from commercially available 2,4,6-trihydroxyacetophenone as a starting material. The isoflavone skeleton of - was constructed by the Suzuki-Miyaura coupling reaction as the key reaction. Investigation of the potential of - as therapeutic agents for transthyretin (TTR) amyloidosis revealed that millexatin F () showed the best efficacy in competitive binding experiments and thioflavin-T fluorescence studies. Therefore, millexatin F () is promising as a seed compound for a novel TTR amyloidosis therapeutic agent.

A comprehensive phytochemical investigation of root extract led to the isolation of two new geranylated xanthones ( and ), one new geranylated flavone (), one new flavanone (), and one unique benzopyran (), along with 16 known compounds. Structures of the new compounds were elucidated by a combination of spectroscopic and computational methods. Two different types of compounds, flavone and arylbenzofuran , displayed the most potent antityrosinase activity with IC values of 1.7 ± 0.2 and 1.2 ± 0.1 μM, respectively. In addition, kinetic measurements and molecular docking simulations of compounds and were performed and revealed that compound is a competitive inhibitor binding with the tyrosinase active site, while compound is a noncompetitive tyrosinase inhibitor binding the enzyme at the allosteric site.

Solanapyrones are metabolites bearing a 3,4-dehydrodecalin moiety isolated from cultures of different fungi that are associated with plant diseases. Research on solanapyrones resulted in the first report of a Diels-Alderase enzyme implicated in natural product biosynthesis related to the formation of the 3,4-dehydrodecalin core. In addition, several total syntheses of solanapyrones have been reported, which are also connected with the formation of the characteristic cycloaddition-derived 3,4-dehydrodecalin moiety. This Review provides the first comprehensive overview on the chemistry, biosynthesis, and biological activities of solanapyrones under the theme of synthetic and biosynthetic research progress on cycloaddition-derived secondary metabolites.

Myxochelins are a group of catecholate siderophores encoded by biosynthetic gene clusters (BGCs). They are mainly produced by myxobacteria and display a wide variety of bioactivities. Herein, we report a group of new myxochelins produced not by a myxobacterial strain but by an actinobacteria strain, sp. TMD166. They consisted of six new compounds, designated as sporachelins A (), A1 (), B (), C (), D (), and E (), and the known compound myxochelin A (). The planar structures were determined by comprehensive analyses of 1D and 2D NMR spectroscopic data, and the absolute configurations were confirmed by Marfey's analysis and chemical synthesis. The six sporachelins are the first examples of acylated derivatives at the primary alcohol of myxochelin A. These molecules were found to inhibit human 5-lipoxygenase. In addition, - exhibited antifibrotic activity in the TGFβ1-induced human hepatic cell line LX-2 by suppressing fibrosis-related genes , , and expression. This is the first report of antifibrotic activity by myxochelins.

There is limited information on interactions between cannabinoids and many pharmacologically and toxicologically relevant targets in humans (e.g., receptors, ion channels, enzymes, and transporters). To address this data gap, seven cannabinoids were screened against a panel of 44 safety-related biological targets in competitive ligand binding or enzymatic activity assays. Diverse binding profiles were observed among the cannabinoids; however, colloidal aggregates were detected by dynamic light scattering and a detergent-sensitive enzyme inhibition assay. These aggregates may nonspecifically inhibit targets, yielding false positives. Although screening identified aggregates, additional testing is required to confirm cannabinoid aggregation in individual assays.

The cyanobacterial dialkylresorcinol bartolosides were initially reported to feature glycosylated and halogenated moieties. Later, biosynthetic and studies showed that the chlorinated alkyl chains are utilized for a nucleophilic substitution with free fatty acid carboxylates from primary metabolism, generating bartoloside esters. Here, we applied a workflow based on PCR screening coupled to LC-HRESIMS and molecular network analysis with the aim of discovering additional bartoloside diversity. We report the annotation of 27 bartoloside and bartoloside ester derivatives, including the characterization of two new bartolosides, underlining the breadth of structures generated by bartoloside biosynthetic pathways. Some of the herein reported bartolosides feature hydroxylation in their side chains, a modification that has not been associated with this metabolite family.

Chemical investigation of the cyanobacterium NIES-4285 led to the isolation of six new natural products, microginins 705 (), 719 (), 733A (), 733B (), and 733C (), and anabaenopeptin 885 (), and three known compounds, anabaenopeptins 871 (), B (), and F (). Planar structures and absolute configurations for - were determined by 2D NMR, HRMS, and Marfey's analyses. Microginin 733C (), and anabaenopeptins 871 () and 885 () contained a unique residue of 2-amino-5-(4-hydroxyphenyl)pentanoic acid (Ahppa): doubly homologated tyrosine (di-hTyr). The biosynthetic origin of this nonproteinogenic amino acid di-hTyr was investigated, and it was found that MaHphABCDE are involved in the production of di-hTyr. In addition, biochemical characterization of aminotransferase MaHphE showed that it is a promiscuous enzyme. This result expanded the biocatalytic toolbox for amino acid homologation.

Natural products (NPs) continue to inform the discovery and development of a diversity of drugs, both marketed and investigational. Pain, one of the most common of human experiences and profound challenges in medicine and biology, has emerged at the core of an urgent societal problem, in the United States and globally. The present study employs a retrospective analysis of an extensive set of published literature curated in the NAPRALERT database to identify NPs with experimental evidence of bioactivity supporting the selection and prioritization of NP leads with promise in pain management. The NAPRALERT pain data set currently documents >38,000 pain-relevant experiments reported in >1,750 distinct journals. The evidence presented here was annotated from >10,000 distinct scientific publications identifying NP extracts and isolates with experimental biological data indicating positive mitigation of pain, inflammation, and/or modulation of nociceptive signaling targets. Correlation of ethnomedical uses with experimental data represents a value-added approach to the selection and prioritization of leads. Dissemination of this unique NP/pain data set, with experimental data and information applicable to basic, translational, and clinical science stakeholders alike, furnishes practical evidence in support of a rational selection of NPs for directed pain research. A large portion of the NAPRALERT pain-relevant data set, along with a set of query tools designed to assist user-directed selection and prioritization of leads, are presented as Supporting Information in order to mitigate the limitations inherent in presenting such a large data set in (print) format. To support user efforts, this report involves explication of NAPRALERT data organization and the articulation of rational approaches to user-guided selection of evidence-based NP leads.

Chemical profiling of soil-derived microbes collected under the auspices of the Australian citizen science initiative Soils for Science detected two fungi, sp. S4S-07771A07 and sp. S4S-14879B01, capable of producing pullenvalenes, a rare class of triterpene glycoside. Cultivation profiling followed by scaled up cultivation and fractionation of the former yielded the known pullenvalenes A-D (-) and the new analogues E-H (-), with structures secured by detailed spectroscopic analysis and biogenetic considerations. This study reveals that the pullenvalenes - are produced by several genera of fungi (, and ) recovered from different geographic locations and substrates. We also draw attention to structural and biosynthetic similarities with the known Red Sea sponge metabolites neviotines A-D (-) and abudinols A-B (-), prompting speculation that the latter may be products of sponge-associated fungi.

The phytochemical investigation of the MeOH extract of roots led to the discovery of a new tetrahydropyran cycloartane-type triterpenoid, astracondensatol A (), alongside six known cyclocephagenol derivatives (, , , , , and ). Elucidation of their structures involved 1D and 2D-NMR spectroscopy and mass data analysis. Upon comparing NMR spectroscopic data with prior literature, several carbon shift anomalies, particularly at C-24, prompted a reevaluation using quantum chemical calculations, resulting in the revision of the 24 to 24 absolute configuration for compound and 38 other reported cyclocephagenol-type triterpenoids. X-ray crystallography data further supported the analysis in establishing the absolute configuration of compound . Ambiguous NOE correlations and publication bias could have played a significant role in miss-assigning the C-24 absolute configuration in tetrahydropyran cycloartane-type triterpenoids.

Chemical profiles of and were investigated, resulting in the isolation of five new discorhabdin D derivatives and -. Their planar structures were solved by combination of NMR and HR-MS, while -based configurational analysis, computational techniques, and semisynthetic methods were used for the establishment of their absolute configurations. New natural products were tested for their growth inhibitory activity against the NCI-60 human tumor cell line panel, and two compounds and showed low micromolar potency.

Terrestrial actinomycetes in the genus have long been recognized as prolific producers of small-molecule natural products, including many clinically important antibiotics and cytotoxic agents. Although can also be isolated from marine environments, their potential for natural product biosynthesis remains underexplored. The MAR4 clade of largely marine-derived has been a rich source of novel halogenated natural products of diverse structural classes. To further explore the biosynthetic potential of this group, we applied pattern-based genome mining, leading to the discovery of the first halogenated pyrroloketoindane natural products, indanopyrrole A () and B (), and the bioinformatic linkage of these compounds to an orphan biosynthetic gene cluster (BCG) in 20 MAR4 genomes. Indanopyrrole A displays potent broad-spectrum antibiotic activity against clinically relevant pathogens. A comparison of the putative indanopyrrole BGC with that of the related compound indanomycin provides new insights into the terminal cyclization and offloading mechanisms in pyrroloketoindane biosynthesis. Broader searches of public databases reveal the rarity of this BGC while also highlighting opportunities for discovering additional compounds in this uncommon class.