Bioactive Precursors Research Articles

Synthesis and molecular docking analysis of MBH adducts' derived amides as potential β-lactamase inhibitors.

Humans suffer from various diseases that require more specific drugs to target them. Among the different potent agents, β-lactamases serve as good antibacterial agents; however, β-lactamases are resistant to such antibiotics. The present study was designed to prepare efficient β-lactamase inhibitor amides (12-15) from inexpensive, easily accessible, and bioactive precursors; Morita Baylis Hillman (MBH) adducts (5-8). The adducts (5-8) were primarily prepared by treating their respective aldehydes with the corresponding acrylate in the presence of an organic Lewis base at ambient temperature. The compounds were characterized using mass spectrometry, FTIR and NMR spectroscopy. Furthermore, in silico studies (using AutoDock Tools and AutoDock Vina programs) on the adduct and corresponding amide product revealed that all MBH adducts (5-8) and their product amides (12-15) are significant inhibitors of β-lactamase. Additionally, among the MBH adducts, adduct 7 showed the highest binding affinity with β-lactamase, whereas amide 15 was identified as a highly potent antibacterial based on its docking score (-8.6). In addition, the absorption, distribution, metabolism, and excretion (ADME) test of the synthesized compounds demonstrated that all compounds showed drug-likeness properties.

Fabrication of iron nanoparticles using different bioactive precursors, their characterization and bioactivity evaluation

This study deals with the green synthesis of Iron nanoparticles (FeNPs) using plant extracts of Polygonum plebeium (Knotweed) and Camellia sinensis (Green tea), focusing on their antibacterial potential, biocatalytic action as well as prospective applications as nanofertilizers. Plant materials underwent a thorough cleaning and were processed into aqueous extracts. The synthesis of FeNPs involved blending these extracts with ferric chloride solution, resulting in a versatile nanomaterial that was subjected to various characterization techniques, such as UV-Vis spectroscopy, FT-IR, XRD, SEM, and DLS-Zeta unveiling critical nanoparticle attributes of the synthesized nanoparticles, including the size, crystallinity, morphology, stability, and elemental composition. The synthesized FeNPs exhibited substantial antibacterial activities, against Escherichia coli and Staphylococcus aureus. Additionally, the biocatalytic properties of the synthesized FeNPs were investigated through dye degradation. These nanoparticles further, were demonstrated for their potential as nanofertilizers, enhancing the germination and growth of tomato and radish seeds. The merging of nanotechnology and plant-based synthesis represents a promising intersection with the capacity to revolutionize diverse fields.

Structure-guided mining and engineering of nicotinamide riboside kinase for efficient synthesis of nicotinamide mononucleotide

Nicotinamide mononucleotide (NMN) is a bioactive precursor to nicotinamide adenine dinucleotide (NAD+) and has demonstrated anti-aging activity. Nicotinamide riboside kinase (NRK) can convert nicotinamide ribose (NR) into NMN in one step, but NRKs with high catalytic efficiency are rare and are difficult to engineer. In this study, two novel NRKs from Sparassis crispa and Beauveria bassiana were identified. They displayed impressive specific activities of 6.14 U/mg and 6.66 U/mg with high substrate (NR) conversion rates. Furthermore, structural modelling analysis and semi-rational design were used to develop variants of BEANRK. Variant M1 (V172K) exhibited a 1.2-fold of the wild-type BEANRK (WT) in enzyme activity and 91 % of substrate conversion rate with improved thermal stability compared to WT. Moreover, variants generated from site-specific mutagenesis were also computationally analyzed to elucidate which interactions between key amino residues and substrates facilitated an increase in catalytic activity and conversion rate. This study not only identified new NRKs but also provided insights into which amino acid residues were pivotal to the catalytic activity of NRK, paving the way for future NRK engineering to improve the industrial production of NMN.

Farnesoid X receptor regulators from natural products and their biological function.

Metabolic syndrome (MetS) has been a growing public health concern worldwide without specific medicine. Through summarizing the chemical structure type and effect mechanisms of natural products targeted on farnesoid X receptor (FXR), to provide the research basis for exploring the treatment of MetS. The following databases were searched for natural products which targeting FXR: PubMed, Embase, the Cochrane Library, Web of Science, China National Knowledge Infrastructure Database, Wanfang Database, China Science and Technology Journal Database, and Chinese Biomedical Literature Database. Totally 120 natural products were summarized, including terpenoids (51 compounds), steroidal saponins (27 compounds), phenylpropanolds (19 compounds), flavonoids (13 compounds), alkaloids (3 compounds) and others (7 compounds), most researches focus on terpenoids and part of synthetic FXR regulators were based on the structure of terpenoids. FXR regulators could improve cholestasis and liver injury, hyperlipidemia, diabetes and atherosclerosis. FXR is a potential target of treating MetS. Natural products are characteristics with unique novel structures and special biological activity, and they are important sources of bioactive precursor compounds and drug discovery. Exploring the effects and mechanism of natural products and its derivative on MetS by targeting FXR may be a new way to develop the new drugs of treating MetS.

Electrocatalytic hydrogenation of quinolines with water over a fluorine-modified cobalt catalyst

Room temperature and selective hydrogenation of quinolines to 1,2,3,4-tetrahydroquinolines using a safe and clean hydrogen donor catalyzed by cost-effective materials is significant yet challenging because of the difficult activation of quinolines and H2. Here, a fluorine-modified cobalt catalyst is synthesized via electroreduction of a Co(OH)F precursor that exhibits high activity for electrocatalytic hydrogenation of quinolines by using H2O as the hydrogen source to produce 1,2,3,4-tetrahydroquinolines with up to 99% selectivity and 94% isolated yield under ambient conditions. Fluorine surface-sites are shown to enhance the adsorption of quinolines and promote water activation to produce active atomic hydrogen (H*) by forming F−-K+(H2O)7 networks. A 1,4/2,3-addition pathway involving H* is proposed through combining experimental and theoretical results. Wide substrate scopes, scalable synthesis of bioactive precursors, facile preparation of deuterated analogues, and the paired synthesis of 1,2,3,4-tetrahydroquinoline and industrially important adiponitrile at a low voltage highlight the promising applications of this methodology.

Dynamics of different ion release from denture-base acrylic resins and their mechanical properties after the addition of bioactive materials

BackgroundThe denture-base acrylic resins used by partially edentulous patients can cause local demineralization of teeth. Alkali ions released from the bioactive materials that were added to acrylic resins can increase the pH of the oral environment and slow down the demineralization process. Aim of the studyThis study aimed to create a new denture-base acrylic resin that can release ions. Materials and methodsA total of 222 samples with different fillers (calcium hydrogen phosphate, hydroxyapatite, two kinds of bioactive glasses, and a product obtained by reaction between bioactive glass formed from glass ionomer cement and polyacrylic acid) were prepared for the study. All the materials were tested for mechanical properties and their use as phosphate donors for 3 weeks. The measurements were presented as mean ± SD error of the mean. Data were analyzed by two-way analysis of variance, with a p-value of <0.05 as statistically significant. ResultsAcrylic resins obtained after the addition of a small quantity of bioactive materials (2.5–5%) showed similar mechanical properties (such as flexural strength and Izod impact resistance) as non-filled material. However, the hardness of the modified materials was higher compared to pure poly (methyl methacrylate). Samples modified with materials released phosphate ions for a short period. The materials that were identified to be most promising as an ion source were samples containing 5% calcium hydrogen phosphate (p < 0.01). ConclusionsBased on the results, it can be concluded that denture-base acrylic resins resulting after the addition of different bioactive precursors have improved mechanical properties and can release ions to the oral environment for a short period.

Interleukin 1α: a comprehensive review on the role of IL-1α in the pathogenesis and treatment of autoimmune and inflammatory diseases.

The interleukin (IL)-1 family member IL-1α is a ubiquitous and pivotal pro-inflammatory cytokine. The IL-1α precursor is constitutively present in nearly all cell types in health, but is released upon necrotic cell death as a bioactive mediator. IL-1α is also expressed by infiltrating myeloid cells within injured tissues. The cytokine binds the IL-1 receptor 1 (IL-1R1), as does IL-1β, and induces the same pro-inflammatory effects. Being a bioactive precursor released upon tissue damage and necrotic cell death, IL-1α is central to the pathogenesis of numerous conditions characterized by organ or tissue inflammation. These include conditions affecting the lung and respiratory tract, dermatoses and inflammatory skin disorders, systemic sclerosis, myocarditis, pericarditis, myocardial infarction, coronary artery disease, inflammatory thrombosis, as well as complex multifactorial conditions such as COVID-19, vasculitis and Kawasaki disease, Behcet's syndrome, Sjogren Syndrome, and cancer. This review illustrates the clinical relevance of IL-1α to the pathogenesis of inflammatory diseases, as well as the rationale for the targeted inhibition of this cytokine for treatment of these conditions. Three biologics are available to reduce the activities of IL-1α; the monoclonal antibody bermekimab, the IL-1 soluble receptor rilonacept, and the IL-1 receptor antagonist anakinra. These advances in mechanistic understanding and therapeutic management make it incumbent on physicians to be aware of IL-1α and of the opportunity for therapeutic inhibition of this cytokine in a broad spectrum of diseases.

Re-wiring the regulation of the formicamycin biosynthetic gene cluster to enable the development of promising antibacterial compounds

SummaryThe formicamycins are promising antibiotics first identified in Streptomyces formicae KY5, which produces the compounds at low levels. Here, we show that by understanding the regulation of the for biosynthetic gene cluster (BGC), we can rewire the BGC to increase production levels. The for BGC consists of 24 genes expressed on nine transcripts. The MarR regulator ForJ represses expression of seven transcripts encoding the major biosynthetic genes as well as the ForGF two-component system that initiates biosynthesis. We show that overexpression of forGF in a ΔforJ background increases formicamycin production 10-fold compared with the wild-type. De-repression, by deleting forJ, also switches on biosynthesis in liquid culture and induces the production of additional, previously unreported formicamycin congeners. Furthermore, combining de-repression with mutations in biosynthetic genes leads to biosynthesis of additional bioactive precursors.

ActDES - a curated Actinobacterial Database for Evolutionary Studies.

Actinobacteria is a large and diverse phylum of bacteria that contains medically and ecologically relevant organisms. Many members are valuable sources of bioactive natural products and chemical precursors that are exploited in the clinic and made using the enzyme pathways encoded in their complex genomes. Whilst the number of sequenced genomes has increased rapidly in the last 20 years, the large size, complexity and high G+C content of many actinobacterial genomes means that the sequences remain incomplete and consist of large numbers of contigs with poor annotation, which hinders large-scale comparative genomic and evolutionary studies. To enable greater understanding and exploitation of actinobacterial genomes, specialized genomic databases must be linked to high-quality genome sequences. Here, we provide a curated database of 612 high-quality actinobacterial genomes from 80 genera, chosen to represent a broad phylogenetic group with equivalent genome re-annotation. Utilizing this database will provide researchers with a framework for evolutionary and metabolic studies, to enable a foundation for genome and metabolic engineering, to facilitate discovery of novel bioactive therapeutics and studies on gene family evolution. This article contains data hosted by Microreact.

Halogenases for biosynthetic pathway engineering: Toward new routes to naturals and non-naturals

ABSTRACT Nature’s repertoire of bio-halogenase enzymes is intriguing with halogenases from various natural product biosynthetic clusters that carry out site and region-specific halogenation of diverse bioactive precursors and molecules. Currently, we have a comprehensive catalogue of cryptic and non-cryptic halogenases that act on simple to complex aliphatic and aromatic molecular scaffolds. This will open up further synthetic and biosynthetic opportunities for C-H activation, ring formation and functionalization of different molecular structures. In fact, halogenases were exploited over the years for these potential applications, to replace traditional chemical halogenation chemistries toward creating economical and environmentally benign methodologies and also for biosynthetic pathways. This review will discuss our advances in utilizing bio-halogenases to generate both in vivo and in vitro biosynthetic pathways; summarizing all naturals and non-naturals that are synthesized with a direct bio-halogenase incorporation.

High-level expression of aryl-alcohol oxidase 2 from Pleurotus eryngii in Pichia pastoris for production of fragrances and bioactive precursors

The fungal secretome comprises various oxidative enzymes participating in the degradation of lignocellulosic biomass as a central step in carbon recycling. Among the secreted enzymes, aryl-alcohol oxidases (AAOs) are of interest for biotechnological applications including production of bio-based precursors for plastics, bioactive compounds, and flavors and fragrances. Aryl-alcohol oxidase 2 (PeAAO2) from the fungus Pleurotus eryngii was heterologously expressed and secreted at one of the highest yields reported so far of 315 mg/l using the methylotrophic yeast Pichia pastoris (recently reclassified as Komagataella phaffii). The glycosylated PeAAO2 exhibited a high stability in a broad pH range between pH 3.0 and 9.0 and high thermal stability up to 55 °C. Substrate screening with 41 compounds revealed that PeAAO2 oxidized typical AAO substrates like p-anisyl alcohol, veratryl alcohol, and trans,trans-2,4-hexadienol with up to 8-fold higher activity than benzyl alcohol. Several compounds not yet reported as substrates for AAOs were oxidized by PeAAO2 as well. Among them, cumic alcohol and piperonyl alcohol were oxidized to cuminaldehyde and piperonal with high catalytic efficiencies of 84.1 and 600.2 mM−1 s−1, respectively. While the fragrance and flavor compound piperonal also serves as starting material for agrochemical and pharmaceutical building blocks, various positive health effects have been attributed to cuminaldehyde including anticancer, antidiabetic, and neuroprotective effects. PeAAO2 is thus a promising biocatalyst for biotechnological applications.Key points• Aryl-alcohol oxidase PeAAO2 from P. eryngii was produced in P. pastoris at 315 mg/l.• Purified enzyme exhibited stability over a broad pH and temperature range.• Oxidation products cuminaldehyde and piperonal are of biotechnological interest.Graphical abstract

Potency of Protein Cocoa Beans as Food Bioactive Precursor to Prevent Hypertension

Cocoa beans are superior plantation commodity in Indonesia. The fermentation practice on cocoa beans process has a very important role not only to produce quality seeds but also bioactive peptides. Proteolysis that occurs during cocoa fermentation can produce peptide fragments that have health benefits, such as antihypertension. Hypertension is a major risk factor for cardiovascular diseases and has an important impact on public health. Scientific research gathered strong evidence about the role of cocoa beans peptide involved in biochemical pathways in the control of blood pressure that is endothelin converting enzyme systems. This paper describes the current literature that explain potency of protein cocoa beans in action on angiotensin converting enzyme inhibition, that might antihypertensive effects of biologically active peptides from cocoa beans.

Exploring the Antiangiogenic Potential of Solomonamide A Bioactive Precursors: In Vitro and in Vivo Evidences of the Inhibitory Activity of Solo F-OH During Angiogenesis.

Marine sponges are a prolific source of bioactive compounds. In this work, the putative antiangiogenic potential of a series of synthetic precursors of Solomonamide A, a cyclic peptide isolated from a marine sponge, was evaluated. By means of an in vitro screening, based on the inhibitory activity of endothelial tube formation, the compound Solo F–OH was selected for a deeper characterization of its antiangiogenic potential. Our results indicate that Solo F–OH is able to inhibit some key steps of the angiogenic process, including the proliferation, migration, and invasion of endothelial cells, as well as diminish their capability to degrade the extracellular matrix proteins. The antiangiogenic potential of Solo F–OH was confirmed by means of two different in vivo models: the chorioallantoic membrane (CAM) and the zebrafish yolk membrane (ZFYM) assays. The reduction in ERK1/2 and Akt phosphorylation in endothelial cells treated with Solo F–OH denotes that this compound could target the upstream components that are common to both pathways. Taken together, our results show a new and interesting biological activity of Solo F–OH as an inhibitor of the persistent and deregulated angiogenesis that characterizes cancer and other pathologies.

OBTAINING OF Β-LACTOGLOBULIN BY GEL FILTRATION OF COW MILK WHEY

Milk whey proteins carry out a number of important biological functions and also they are precursors of many biologically active peptides (antihypertensive peptides, antagonists of opioid receptors, regulators of intestinal motility, immunomodulatory, anti-microbial and anti-cancer peptides, appetite regulators and so on.). An important stage in natural bioactive peptides obtaining from milk whey proteins is the isolation of homogeneous proteins-precursors. Considering the significant difference in the molecular masses of whey proteins, a promising method for their selection is gel filtration. The purpose of the research was the fractionation of bioactive peptides precursors from milk whey using gel filtration on Sephadex G-150. The whey was obtained from fresh skimmed milk after isoelectric precipitation of casein. Gel filtration was carried out on the columns from a liquid chromatography kit by the “Reanal” company. The fractional composition and the degree of homogeneity of milk whey proteins were determined by disc-electrophoresis in the plates of a polyacrylamide gel. A repeated gel filtration of fractions from the chromatographic peaks, separated into sections, was performed to increase the fractionation efficiency. While choosing a dextran gel for gel filtration of precursors of biologically active peptides from milk whey proteins, we have taken into account the range of their molecular weights (from 10000 to 150000 Da), the ability to form supramolecular structures (β-LG), as well as the previously obtained results of gel filtration. As a result, it was shown that repeated gel filtration of milk whey on Sephadex G-150 allows efficiently fractionate the proteins-precursors of bioactive peptides. The range of peptides and proteins molecular weights that can be fractionated on this Sephadex is from 5000 to 300 000 Da. The usage of repeated gel filtration on Sephadex G-150 with the chromatogram separation into sectors allows to effectively fractionate proteins-precursors of bioactive peptides from milk whey. In particular, homogeneous β-lactoglobulin (degree of homogeneity &gt; 95 %) and partially purified α-lactalbumin, as well as a group of immunoglobulins and a proteose-peptone fraction were obtained.

Methyl-2-formyl benzoate: A Review of Synthesis and Applications

Methyl-2-formyl benzoate is known as a bioactive precursor in organic synthesis of compounds due to its variety of pharmacological activities namely antifungal, antihypertensive anticancer, antiulcer, antipsychotic and antiviral properties. As an active scaffold, methyl-2-formyl benzoate can be considered as a significant structure and an excellent precursor for the search of new bioactive molecules. Methyl-2-formyl benzoate is synthetically a versatile substrate, which can be used as a raw material for the preparation of medical products. Due to its significant in organic synthesis, the objective of this review is to discuss on the various synthetic routes for the preparation of methyl2-formyl benzoate (via two-step and one-step methodologies) and its importance as precursor for the preparation of compounds with pharmaceutical applications. This review is of importance in synthetic fields and pharmaceutical industry.

Synthesis of silver nanoparticles from a bioactive precursor

Abstract Silver nanoparticles are well known for their medicinal properties from time immemorial. Improving their potential applications demands a greener approach to synthesise them. Embelin, a bioactive molecule belonging to the Myrsinaceae family has gained considerable research interest over the past few years due to its diverse properties as anti-inflammatory, antitumour, analgesic and antimicrobial agent. Being an antioxidant, embelin is capable of reducing metal to metal nanoparticles. In this report, reduction of silver to silver nanoparticles has been carried out using embelin. The silver nanoparticles thus formed were characterised using absorption spectroscopy as well as TEM measurement. The synergic effect on the activity of the silver-embelin system is compared with pure embelin

Natural Product-Based 1,2,3-Triazole/Sulfonate Analogues as Potential Chemotherapeutic Agents for Bacterial Infections.

Despite the vast availability of antibiotics, bacterial infections remain a leading cause of death worldwide. In an effort to enhance the armamentarium against resistant bacterial strains, 1,2,3-triazole (5a–x) and sulfonate (7a–j) analogues of natural bioactive precursors were designed and synthesized. Preliminary screening against two Gram-positive (Streptococcus pneumoniae and Enterococcus faecalis) and four Gram-negative bacterial strains (Pseudomonas aeruginosa, Salmonella enterica, Klebsiella pneumoniae, and Escherichia coli) was performed to assess the potency of these analogues as antibacterial agents. Among all triazole analogues, 5e (derived from carvacrol) and 5u (derived from 2-hydroxy 1,4-naphthoquinone) bearing carboxylic acid functionality emerged as potent antibacterial agents against S. pneumoniae (IC50: 62.53 and 39.33 μg/mL), E. faecalis (IC50: 36.66 and 61.09 μg/mL), and E. coli (IC50: 15.28 and 22.57 μg/mL). Furthermore, 5e and 5u also demonstrated moderate efficacy against multidrug-resistant E. coli strains and were therefore selected for further biological studies. Compound 5e in combination with ciprofloxacin displayed a synergistic effect on multidrug-resistant E. coli MRA11 and MRC17 strains, whereas compound 5u was selective against E. coli MRA11 strain. Growth kinetic studies on S. pneumoniae and E. coli treated with 5e and 5u showed an extended lag phase. 5e and 5u did not show significant cytotoxicity up to 100 μg/mL concentration on human embryonic kidney (HEK293) cells. Transmission electron microscopic (TEM) analysis of bacterial cells (S. pneumoniae and E. coli) exposed to 5e and 5u clearly showed morphological changes and damaged cell walls. Moreover, these compounds also significantly inhibited biofilm formation in S. pneumoniae and E. coli strains, which was visualized by scanning electron microscopic (SEM) analysis. Treatment of larvae of Galleria mellonella (an in vivo model for antimicrobial studies) with 5e and 5u did not cause an alteration in the hemocyte density, thereby indicating lack of an immune response, and were nontoxic up to a concentration of 2.5 mg/mL.

Exploring the Ring-Closing Metathesis for the Construction of the Solomonamide Macrocyclic Core: Identification of Bioactive Precursors.

New synthetic strategies directed toward the novel cyclopeptides solomonamides have been explored utilizing an olefin metathesis as the key reaction. In the various strategies investigated, we worked on minimally oxidized systems, and the olefin metathesis reaction demonstrated efficiency and validity for the construction of the macrocyclic core. The described synthetic strategies toward the solomonamides are well suited for the subsequent access to the natural products and represent flexible and diversity-oriented routes that allow for the generation of a variety of analogues via oxidative transformations. In addition, preliminary biological evaluations of the generated solomonamide precursors revealed antitumor activity against various tumor cell lines.

Extraction and Quantification of Bioactive Tyrian Purple Precursors: A Comparative and Validation Study from the Hypobranchial Gland of a Muricid Dicathais orbita.

Muricidae are marine molluscs known for the production of Tyrian purple and bioactive precursor compounds. A validation study for the extraction and analysis of secondary metabolites found in the hypobranchial gland of the muricid Dicathais orbita is reported, using high performance liquid chromatography–mass spectrometry (HPLC-MS) with diode array detector (DAD). Quantification of the dominant secondary metabolites from D. orbita is described, followed by a comparison of solvent extraction procedures and stability studies. The intra- and inter-day relative standard deviation (RSD) for tyrindoxyl sulphate was 0.46% and 0.17%, respectively. The quantification was linear for standards murexine, 6-bromoisatin, and tyrindoxyl sulphate. The limits of detection were 0.03, 0.004, and 0.07 mg/mL, respectively, and the limits of quantification were 0.09, 0.01, and 0.22 mg/mL, respectively. The results showed that alcoholic solvents were better for extracting choline ester and indoxyl sulphate ultimate precursors, while chloroform was more suitable for the extraction of the intermediate precursors. Multivariate analysis revealed significant differences in extract composition according to the solvent used. Stability testing showed an increase of the oxidative compounds 6-bromoisatin and putative tyrindoxyl S-oxide sulphate in the ethanol extracts while more degradation products were seen in the chloroform extracts after months of cold storage. The validated method was found to be simple, reproducible, precise, and suitable for quantification of the secondary metabolites of muricid molluscs for dye precursor and nutraceutical quality control, as well as applications in marine chemical ecology.

Peptidome Analysis of Human Milk β-Casein in vitro Neonatal Digestive Model by Matrix-assisted Laser Desorption/Ionization-Time-of-Flight Tandem Mass Spectrometry

Abstract Human milk β-casein was digested in vitro by simulated neonatal digestive model to explore the peptidome of human β-casein digested in neonate by matrix-assisted laser desorption/ionization-time-of-flight tandem mass spectrometry (MALDI-TOF/TOF). The accelerating voltage was 20 kV. The laser wavelength was 337 nm and the frequency was 200 Hz. Ion extraction delay was 330 ns. Final mass spectra were produced by averaging 2000 laser shots taken at five different positions within each spot. The peptides scanning range is from m/z 500 to m/z 5000. A total of 26 peptides were identified in the molecular weight range of 1000–4000 Da, and no bioactive peptides were found. Instead, we found nine bioactive peptide precursors which include four ACE (Angiotensin converting enzyme) inhibitory peptide precursors, two CPP (Caseinophosphopeptide) precursors, two antioxidant peptide precursor and one immune active peptide precursor. Most of the bioactive peptide precursors might be further digested into biologically active peptides by proteases according to the present cleavage sites.