Natural Products Research Articles

To Gibbs or Not to Gibbs Effect of Entropic Contribution in the NMR Calculations of Flexible and Polar Molecules-Updating the DP4+App.

The application of quantum-based NMR methods for the structural elucidation of natural and unnatural products has grown significantly. However, accurately calculating the conformational landscape of flexible molecules with intricate intramolecular hydrogen bonding (IHB) networks continues to be a major challenge. In this work, we thoroughly studied the effect of entropic contributions (trough Gibbs free energies calculations) in the DP4+ performance. Our results show that to solve biased systems with strong IHB interactions requires computing the Boltzmann contributions using Gibbs free energies computed with at least triple-ξ basis set and SMD solvation model. In response to this finding, we have updated our DP4+App, a user-friendly Python applet that automates the entire process of calculating DP4+ probabilities. In the new version, the program allows for calculating of conformational contributions at any selected theory level, using either SCF or Gibbs free energies.

Formulation and evaluation of herbal makeup primer

The burgeoning interest in natural and sustainable beauty products has driven the development of herbal makeup primers, which combine cosmetic functionality with the benefits of botanical ingredients. This abstract explores the formulation, efficacy, and advantages of herbal makeup primers. Unlike traditional primers that often rely on synthetic chemicals, herbal primers leverage plant-based extracts known for their skin-enhancing properties, such as aloe Vera& Orange oil. These ingredients offer soothing, anti-inflammatory, and antioxidant benefits that can improve skin texture and promote a healthier complexion. The formulation of herbal makeup primers typically includes a blend of herbal extracts, essential oils, and natural emulsifiers. These components work synergistically to create a smooth base for makeup application while also addressing skin concerns such as redness, dryness, and uneven tone. Clinical and consumer studies suggest that herbal primers can enhance makeup longevity and performance, while simultaneously contributing to overall skin health. In summary, herbal makeup primers represent a significant advancement in cosmetics science by integrating the therapeutic benefits of herbal ingredients into everyday beauty routines. Their growing popularity underscores a shift towards more eco-friendly and skin-conscious beauty solutions, aligning with consumer demand for products that offer both cosmetic and therapeutic benefits. Future research and development in this field are likely to expand the range of available formulations and further validate the efficacy of these natural alternatives.

Identification of active ingredients in Naomaitai capsules using high-resolution mass spectrometry unite molecular network analysis and prediction of their action mechanisms.

Although Naomaitai capsule (NMC) is widely used in clinical practice and has a good curative effect for cerebral infarction, its material basis and mechanism of action remain unclear. In this study, ultra-high-performance liquid chromatography (UHPLC) coupled with quadrupole Orbitrap MS technology was used to analyse the in vivo and in vitro components of NMC, and the Global Natural Products Social Molecular Networking website was used to further analyse the components of NMC. Next, systems biology approaches were employed to investigate the mechanism of action of NMC. Finally, molecular docking technology was used to verify the network pharmacological results. In total, 177 compounds were identified in vitro, including 65 terpenoids, 62 flavonoids, 25 organic acids and 11 quinones. 64 compounds were identified in the blood of mice, and the main active components included ginkgolide C, ginkgolide A, ligustilide, tanshinone IIB, olmelin, emodin and puerarin. The main targets in vivo included TP53, SRC, STAT3, PIK3CA and PIK3R1. In conclusion, this study has revealed that NMC acts on multiple targets in the body through various active components, exerting synergistic effects in the treatment of CI. Its mechanism of action may involve inhibiting neuronal apoptosis, oxidative stress and inflammatory responses as well as reducing cerebral vascular permeability and promoting cerebral vascular regeneration.

C–H Functionalization of Camphor Through Emerging Approaches

Abstract Camphor and related monoterpenoid natural products have served as versatile “chiral pool” materials in organic chemistry for over half a century. Historically, many researchers have used a variety of transformations involving orchestrated rearrangements of the bornane skeleton to functionalize the camphor framework, expanding the utility of this chiral building block. Recent developments in C–H functionalization methodologies provide myriad opportunities to derivatize the camphor framework in a selective and predictable fashion. In this Review, a short summary of the methods for functionalization of the camphor scaffold using rearrangement chemistry is provided followed by a discussion of emerging methods for directed C–H functionalizations that provide diverse new ways to derivatize the camphor framework.

Halogenated Adenine and Adenosine Natural Products in Streptomyces sp. JCM9888

AbstractAscamycin 1 and dealanylascamycin 2 are adenosine containing nucleoside antibiotics carrying the rare 5’‐O‐sulfamoyl ribose motif and a chlorine atom attached to C2 of the adenine ring. Gene knockouts (ΔacmK and ΔacmJ) in the producing strain, Streptomyces sp. JCM9888, generated mutants that were disabled in the assembly of the sulfamoyl moiety. This resulted in the production of 2‐chloroadenosine 3 and 2‐chloroadenine 4, indicating that purine halogenation can occur independently of sulfamoylation. Incubations in media enriched in bromide content resulted also in the identification of 2‐bromoadenine 5, 2‐bromoadenosine 6 and 5′‐O‐sulfamoyl‐2‐bromoadenosine 7.

Usnic Acid Derivatives as Multi-Target Anti-Alzheimer's Disease Agents: Design, Synthesis, X-Ray Single Crystal Structure of Zn(II) Complex and Biological Activities.

Alzheimer's disease (AD) is multifactorial, which makes the design of multi-target-directed ligands an attractive strategy for the development of anti-AD drugs. In order to enhance the anti-AD effects and reduce the toxicity, two usnic acid (UA) derivatives (1-2) were designed, synthesized and fully characterized by introducing dimethylamine Schiff base moiety into the toxic "triketone" portion. Ellman's method and molecular docking were used to test the cholinesterase inhibitory activities. Antioxidant activities were studied with Fenton reaction, cyclic voltammetry and C. elegans. The results showed that compared with UA, 1-2 had stronger anti-cholinesterase activities and similar antioxidant activities. Notably, solvent evaporation of 2 and ZnCl2 formed a single crystal, which was revealed to be a Zn(II) complex with UA and tertiary amine as mixed ligands by X-ray diffraction. The hydrolysis of 2 was thus furtherly studied by HPLC. Furthermore, the crystal structure supported the replacement of toxic "triketone" moiety in the chelation process, playing a detoxifying role and at the same time regulating metal homeostasis. In silico prediction also showed low hepatotoxicity and acceptable drug-likeness of 1-2. Overall, this work provided useful insights into multi-target anti-AD candidates with the natural product UA as the lead compound.

Selling Natural Laws

This article describes the French naturist milieu of the early 1950s. In line with the questions raised by this special issue, I focus on the commercial structures of naturism, such as the selling of natural products and foods and the renting of bungalows and camping pitches, and on its “guiding function,” namely the rationalization of the irrational through the use of the concept of natural laws and the injunctions stemming out these laws. Based on this case study, I invite the reader to rethink the categorizations of “religion” and “business” by considering what underpins them.

Advancements in Inverse-Electron-Demand Diels–Alder Cycloaddition of 2-Pyrones: Mechanisms, Methodologies

The Diels-Alder (DA) cycloaddition is well-known for its effectiveness in synthesizing natural products and multifunctional materials. This article specifically explores the inverse-electron-demand Diels-Alder (IEDDA) cycloaddition involving 2-pyrones, which display ambiphilic properties due to their unique electronic characteristics. We investigate the mechanisms underlying IEDDA, with a focus on how electron-donating and electron-withdrawing substituents influence reactivity and product selectivity. Various methodologies are reviewed, encompassing non-catalytic and catalytic approaches. Special attention is given to advancements in microwave-assisted techniques and high-pressure conditions, which enhance both reaction efficiency and selectivity. Additionally, the synthesis of chiral bridged bicyclic lactones from substituted 2-pyrones is examined, illustrating their versatility in organic synthesis. This review underscores the significance of IEDDA cycloaddition in pioneering new synthetic routes for building complex molecular structures.

C−X (X=C, O, S, N, B, P) Bond Deuteration and Late‐Stage Applications

AbstractPrecise deuterium labeling has gained significant attentions owing to the wide applications in organic synthesis, medicinal chemistry, and organic materials. C−C and C‐heteroatom bonds constitute the skeleton of organic molecules. This review summarizes the advancements on C−C and C‐heteroatom bond deuterations as well as their applications in late‐stage deuterations of natural products and pharmaceutically relevant molecules.

Current Applications of Organocatalysis in Total Synthesis of Natural Products at Room Temperature

Current Applications of Organocatalysis in Total Synthesis of Natural Products at Room Temperature

Analgesic Effects of Methanol Leaf Extracts from Datura alba ness in Male Wistar Rats through Reduction of C-reactive Protein Levels

Introduction: The increasing interest in utilizing natural products from medicinal plants for pain management stems from their wide availability and minimal side effects. This study aims to evaluate the toxicity profile of Datura alba ness (DAN) extracts and assess their potential analgesic activity through preventive and therapeutic analgesia models in Wistar rats, as well as to investigate the possible mechanisms of action using molecular docking. Materials and Methods: Fresh leaves of DAN were collected from a garden in the Abua/Odua Local Government Area of Rivers State, Nigeria. The leaves were extracted using cold maceration to obtain ethanolic extracts of Datura alba ness (MEDAN). Twelve mice (19-30g) were used for toxicity study, while sixty Wistar rats (140-180g) were used for analgesic studies. Serum C-reactive protein levels were determined using ELISA methods, and molecular docking simulations were conducted using AutoDock and Discovery Studio Visualizer. Results: The results indicated that MEDAN was very safe, with an LD50 of 5000 mg/kg. The findings demonstrate that MEDAN significantly increased the pain threshold in male Wistar rats after three weeks of administration in a dose-dependent manner during the preemptive analgesia study, while pain thresholds increased within one hour but decreased over time in the therapeutic analgesia study. The combination of MEDAN with a standard drug (Flexicam) resulted in improved analgesic effects at the 500 mg/kg dose. Additionally, the study revealed that MEDAN significantly reduced serum C-reactive protein levels after three weeks of oral administration. Molecular docking studies indicated that stigmasterol, gamma-sitosterol, and cholest-5-en-3-ol, 24-propylidene-(3β) from MEDAN demonstrated binding affinity to C-reactive protein receptors, mimicking the effects of the reference drug, celecoxib. Conclusion: This study concludes that ethanolic extracts of Datura alba ness exhibited significant efficacy in pain reduction by lowering C-reactive protein levels. This effect was especially enhanced when the 500 mg/kg dose of MEDAN was combined with the standard drug, Flexicam. The findings provide a scientific basis supporting the traditional medicinal use of Datura alba ness for pain management.

Illuminating Substrate Preferences of Promiscuous F420H2-Dependent Dehydroamino Acid Reductases with 4-Track mRNA Display.

Stereoselective reduction of dehydroamino acids is a common biosynthetic strategy to introduce d-amino acids into peptidic natural products. The reduction, often observed during the biosynthesis of lanthipeptides, is performed by dedicated dehydroamino acid reductases (dhAARs). Enzymes from the three known dhAAR families utilize nicotinamide, flavin, or F420H2 coenzymes as hydride donors, and little is known about the catalysis performed by the latter family proteins. Here, we perform a bioinformatics-guided identification and large-scale in vitro characterization of five F420H2-dependent dhAARs. We construct an mRNA display-based pipeline for ultrahigh throughput substrate specificity profiling of the enzymes. The pipeline relies on a 4-track selection strategy to deliver large quantities of clean data, which were leveraged to build accurate substrate fitness models. Our results identify a remarkably promiscuous enzyme, referred to as MaeJC, that is capable of installing d-Ala residues into arbitrary substrates with minimal recognition requirements. We integrate MaeJC into a thiopeptide biosynthetic pathway to produce d-amino acids-containing thiopeptides, demonstrating the utility of MaeJC for the programmable installation of d-amino acids in ribosomal peptides.

Preclinical Evaluation of Protective Effects of Terpenoids Against Nanomaterial-Induced Toxicity: A Meta-Analysis.

Terpenoids, the largest class of natural products, have been demonstrated to confer antioxidant, anti-inflammatory, anti-apoptotic, and antitumor activities. However, whether terpenoids benefit populations exposed to nanomaterials through these mechanisms remains unclear. This meta-analysis was to evaluate the effects of terpenoids in preclinical models with nanomaterial exposure. Electronic database searching identified 39 studies. The meta-analysis by Stata 15.0 showed that terpenoid supplementation significantly improved cell viability and altered oxidative stress (decreased ROS, NO, MDA, and TOC and increased SOD, CAT, GPx, GSH, GSH-Px, and TAC)-, inflammation (decreased IL-6, IL-1β, TNF-α, NF-κB, monocytes, and increased IL-10)-, apoptosis (reduced Bax, caspase-3, caspase-9, P53, and elevated Bcl-2)-, genotoxic (reduced tail length, % tail DNA, tail moment, DNA fragmentation, chromosomal aberration, and MNPCEs)-, liver function (reduced ALT, AST, and ALP)-, renal function (reduced creatinine, urea, and uric acid)-, reproductive function (increased sperm count, testosterone, Johnsen's score, and number of progeny)-, lipid profile (lower cholesterol, TG, LDL, and higher HDL)-, and carcinogenesis (downregulated AFP and CEA)-related biomarkers induced by nanomaterials. Subgroup analysis indicated that monoterpenoids and tetraterpenoids were particularly effective. Collectively, terpenoids may be a promising candidate for prevention of toxicities caused by nanomaterials.

Study of Electron Beam Irradiated Palladium on Carbon Catalysts for Transfer Hydrogenation Reactions of Nitroarenes Compounds

Palladium-catalyzed hydrogenation is considered a crucial stage in the entire synthesis of difficult natural products as well as a crucial step in the manufacturing of fine compounds used in pharmaceuticals. When it comes to the reaction rate and simplicity of work-up, using Pd/C as heterogeneous catalyst is one of the best choice for process efficiency. In this study, nitroarenes compounds viz. 3-bromo nitrobenzene, 4-fluoro nitrobenzene, 3-methyl nitrobenzene, 4-hydroxy nitrobenzene reduced by using macro 10% Pd/C and micro 10% Pd/C to 3-bromo aniline, 4-fluoro aniline, 3-methyl aniline, 4-hydroxy aniline respectively and verified from 1H NMR studies. The reduction reactions were similar conditions using electron beam irradiated 250 kGy macro and micro 10% Pd/C catalyst. The effectiveness of commercial sources of palladium on carbon (Pd/C) varies widely, leading to the appreciable variations in the reaction times. The decrease in reaction time has been attributed to the higher dispersion of Pd particles upon irradiation. The physico-chemical characteristics of effective hydrogenation catalysts were determined to be: (i) small Pd particle size and (ii) homogeneous distribution of Pd on the carbon support. With no significant loss of catalytic activity, the electron beam-irradiated catalyst can be used again for five runs. These days, chemists can determine as well as forecast the effectiveness of catalysts before investing time and money in expensive synthetic materials.

Anti-gingivitis natural products: Aloe vera gel, tea tree oil mouthwash, turmeric gel, myrrh extract/mouthwash

Gingivitis is an inflammatory gum disease which occurs around the cervical portion of the gum and is classified by its clinical appearance. Gingivitis is very common, and anyone can be affected including but not limited to poor oral care habits. This paper reviews the potential of Aloe Vera, Tea Tree Oil Mouthwash, Turmeric Gel, and Myrrh Extract/Mouthwash. The study also assessed the knowledge and opinions of first-year pharmacy students. The survey part of the study included 5 knowledge-based and 5 opinion-based questions, focusing on the four herbal remedies. The knowledge-based questions showed a 65.7% correct response rate, with the question on turmeric receiving the highest accuracy (94.3%), while the question surveying the participants’ knowledge about the source of information for herbal products received the lowest correct answer rate at 31.4%. Opinion-based questions revealed a positive attitude towards herbal remedies, with about 67.6% to 94.3% strongly agreeing, or agreeing with the potential benefits of the products. The highest agreement rate at 94.3% was obtained for the statement that myrrh can help reduce inflammation in the gums and inhibit the growth of bacteria, thus assisting in the management of gingivitis. Disagreement of opinions was minimal, ranging from 5.7% to 32.3%, indicating a widespread inclination towards positive agreement.

Inoculation of Arthrobacter sp. improves the growth of Acanthocalycium sp. and the fruits nutraceutical quality and the flowers longevity

Research objective: The aim of this work is on the inoculation in the growing medium of Arthrobacter sp. and its effects on the growth, flower quality and longevity of cactus plants. To this end, the study of biometric parameters, i.e. plants and flowers (height, weight, number and duration), as well as root growth (weight), and the presence of disease were quantified as measures of plant productivity and compared with those obtained from non-inoculated plants. The use of alginate microspheres as a means of bacterial inoculation was also considered. Materials and Methods: Seedlings of Acanthocalycium (2 years old) Ferrarii, A. Glaucum and A. Violaceum were immediately planted in pots after purchase, in substrate containing (sand 20%, pumice 20% and peat 60%; pH 7; electrical conductivity 0.7 dS/m; total porosity 80% (v/v). A randomised complete block design was applied for the experiments: the pots were randomly divided into two series, one series was inoculated with the bacteria and the other non-inoculated was used as a control. Each month, plant growth was assessed according to (1) plant height, (2) vegetative and root weight, (3) number of flowers per plant (4) flower duration. In addition, the occurrence of possible diseases, in particular Fusarium sp. and Verticillium sp., was assessed. Total flavonoids, total phenols and antioxidant activity were also analysed. Results and Discussion: The experiment showed that the use of Arthrobacter sp. can indeed significantly improve the vegetative and root growth of Acanthocalycium sp. cacti. In addition, there was a significant improvement in the number and floral longevity as well as in the phenol, flavonoid and antioxidant content of the fruits of the inoculated plants compared to the untreated control. The experiment also showed that mortality due to the pathogens Fusarium sp. and Verticillium sp. was significantly reduced in the treated plant. In agreement with these authors, we found that PGPB treatments increased agronomic parameters and improved Fusarium and Verticillium resistance. In general, the application of biostimulants can increase the synthesis of bioactive compounds in plants by increasing resistance to phytopathologies. Inoculation with Arthrobacter sp. led to a significant reduction in the number of dead plants with respect to the diseases analysed. As a result of the stimulating action demonstrated in Acanthocalycium, bioproducts suitable for nutraceutical purposes may be developed in the future. Therefore, new microbe-assisted technologies can help plants to resist stress conditions, improving their tolerance and productivity. Conclusions: Due to its ‘multifunctionality’, the genus Acanthocalycium is considered as one of the species of the future, for ornamental use and medicinal aspects, and new results may help reveal its potential in the context of the bio-economy and circular economy. As natural resources and cultural practices are crucial in defining the quality of flowers when destined for food/nutraceutical applications, the inoculation of Acanthocalycium with Arthrobacter sp. can be envisaged to provide better plant growth under conditions of environmental stress, or as a soil fertiliser, but also to improve the synthesis of natural products used for therapeutic applications.

Natural Products with Potential for the Treatment of Pain: Global Evidence from the NAPRALERT Database.

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.

Fragment Library of Colombian Natural Products: Generation and Comparative Chemoinformatic Analysis

Fragment libraries have a major significance in drug discovery due to their role in de novo design and enumerating large and ultra-large compound libraries. Although several fragment libraries are commercially available, most are derived from synthetic compounds. The number of fragment libraries derived from natural products is still being determined. Still, they represent a rich source of building blocks to generate pseudo-natural products and bioactive synthetic compounds inspired by natural products. In this work, we generated and analyzed a fragment library of natural products from Colombia, a highly diverse geographical region where fragment libraries are yet to be reported. We also generated and reported fragment libraries of three novel natural product libraries and, as a reference, the most updated version of FDA-approved drugs. In line with the principles of open science, the fragment libraries developed in this study are freely available.

Unlocking Fungal Potential: The CRISPR-Cas System as a Strategy for Secondary Metabolite Discovery

Natural products (NPs) are crucial for the development of novel antibiotics, anticancer agents, and immunosuppressants. To highlight the ability of fungi to produce structurally diverse NPs, this article focuses on the impact of genome mining and CRISPR-Cas9 technology in uncovering and manipulating the biosynthetic gene clusters (BGCs) responsible for NP synthesis. The CRISPR-Cas9 system, originally identified as a bacterial adaptive immune mechanism, has been adapted for precise genome editing in fungi, enabling targeted modifications, such as gene deletions, insertions, and transcription modulation, without altering the genomic sequence. This review elaborates on various CRISPR-Cas9 systems used in fungi, notably the Streptococcus pyogenes type II Cas9 system, and explores advancements in different Cas proteins for fungal genome editing. This review discusses the methodologies employed in CRISPR-Cas9 genome editing of fungi, including guide RNA design, delivery methods, and verification of edited strains. The application of CRISPR-Cas9 has led to enhanced production of secondary metabolites in filamentous fungi, showcasing the potential of this system in biotechnology, medical mycology, and plant pathology. Moreover, this article emphasizes the integration of multi-omics data (genomics, transcriptomics, proteomics, and metabolomics) to validate CRISPR-Cas9 editing effects in fungi. This comprehensive approach aids in understanding molecular changes, identifying off-target effects, and optimizing the editing protocols. Statistical and machine learning techniques are also crucial for analyzing multi-omics data, enabling the development of predictive models and identification of key molecular pathways affected by CRISPR-Cas9 editing. In conclusion, CRISPR-Cas9 technology is a powerful tool for exploring fungal NPs with the potential to accelerate the discovery of novel bioactive compounds. The integration of CRISPR-Cas9 with multi-omics approaches significantly enhances our ability to understand and manipulate fungal genomes for the production of valuable secondary metabolites and for promising new applications in medicine and industry.

Organophotocatalyst Enabled Deoxycyclopropanation of Alcohols.

Cyclopropane fragments, which widely exist in marketed drugs and natural products, can confer special pharmacological properties to small-molecule drugs. Therefore, developing methods to construct cyclopropanes is of great significance. Nevertheless, the introduction of cyclopropane primarily relies on already-formed cyclopropyl groups, which significantly restricts the diversity of cyclopropane skeletons. Late-stage direct cyclopropanation is still a challenging task. Herein, a photo-induced intermolecular deoxycyclopropanation reaction that employs alcohols as substrates, and 1 mol.% of 2,3,5,6-tetrakis(carbazol-9-yl)-1,4-dicyanobenzene (4CzTPN)as organophotocatalyst is reported. This method proceeds with high transformation efficiency (up to 98% yield) and exhibits broad functional group tolerance, such as primary, secondary, and tertiary alcohols as well as various activated β-halogenated alkenes. This process is mild, easy to operate, and has low equipment requirements. The power of this technology is demonstrated by the late-stage functionalization of five marketed drugs and five natural products.