Discovery Of Bioactive Compounds Research Articles

Screening prolyl hydroxylase domain 2 inhibitory activity of traditional Chinese medicine by CZE-UV.

Prolyl hydroxylase domain 2 (PHD2) is a key enzyme regulating the expression of hypoxia inducible factor (HIF). Its inhibitors can improve the expression of HIF and downstream genes, which can treat hypoxia-related diseases. Therefore, the establishment of a reliable PHD2 inhibitors screening method is of great significance for the drug development of hypoxia-related diseases. In this work, an accurate, rapid, and simple screening method for PHD2 inhibitors was introduced by capillary zone electrophoresis (CZE). In order to improve the detection sensitivity, the derivative reaction of α-ketoglutaric acid (α-OG) and 1,2-diaminobenzene (OPD) was used to enhance the UV absorption of α-OG (the substrate in the enzymatic reaction). The CZE method selected 20mM Na2 B4 O7 buffer (pH9.0) as the separation buffer, +25kV as the separation voltage, 25°Cas the cartridge temperature, and 210nm as the detection wavelength. Under this condition, the analysis of a single sample can be realized within 9min. Compared with the existing reported methods, the present work can directly screen the PHD2 inhibitory activity of traditional Chinese medicine (TCM) extracts, which is of significance for the target-purification of bioactive individual compounds from TCMs. Under the optimal conditions, the PHD2 inhibitor screening platform was successfully established, and it was found that 70% methanol/water extracts of Astragali Radix and Codonopsis pilosula had good PHD2 inhibitory activity. Furthermore, the present work provides a novel approach for screening the PHD2 inhibitory activity of TCM extracts and the discovery of anti-hypoxia bioactive compounds.

Recent Advances in Biocatalysis for Drug Synthesis.

Biocatalysis is constantly providing novel options for the synthesis of active pharmaceutical ingredients (APIs). In addition to drug development and manufacturing, biocatalysis also plays a role in drug discovery and can support many active ingredient syntheses at an early stage to build up entire scaffolds in a targeted and preparative manner. Recent progress in recruiting new enzymes by genome mining and screening or adapting their substrate, as well as product scope, by protein engineering has made biocatalysts a competitive tool applied in academic and industrial spheres. This is especially true for the advances in the field of nonribosomal peptide synthesis and enzyme cascades that are expanding the capabilities for the discovery and synthesis of new bioactive compounds via biotransformation. Here we highlight some of the most recent developments to add to the portfolio of biocatalysis with special relevance for the synthesis and late-stage functionalization of APIs, in order to bypass pure chemical processes.

Epigenetic Modification: A Key Tool for Secondary Metabolite Production in Microorganisms.

Microorganisms are stupendous source of secondary metabolites, having significant pharmaceutical and industrial importance. Genome mining has led to the detection of several cryptic metabolic pathways in the natural producer of secondary metabolites (SMs) such as actinobacteria and fungi. Production of these bioactive compounds in considerable amount is, however, somewhat challenging. This led to the search of using epigenetics as a key mechanism to alter the expression of genes that encode the SMs toward higher production in microorganisms. Epigenetics is defined as any heritable change without involving the changes in the underlying DNA sequences. Epigenetic modifications include chromatin remodeling by histone posttranslational modifications, DNA methylation, and RNA interference. Biosynthetic gene cluster for SMs remains in heterochromatin state in which the transcription of constitutive gene is regulated by epigenetic modification. Therefore, small-molecule epigenetic modifiers, which promote changes in the structure of chromatin, could control the expression of silent genes and may be rationally employed for discovery of novel bioactive compounds. This review article focuses on the types of epigenetic modifications and their impact on gene expression for enhancement of SM production in microorganisms.

Assessing Microbial Metabolic and Biological Diversity to Inform Natural Product Library Assembly.

The pressing need for novel chemical matter to support bioactive compound discovery has led natural product researchers to explore a wide range of source organisms and environments. One of the implicit guiding principles behind those efforts is the notion that sampling different environments is critical to accessing unique natural products. This idea was tested by comparing fungi from disparate biomes: aquatic sediments from Lake Michigan (USA) and terrestrial samples taken from the surrounding soils. Matched sets of Penicillium brevicompactum, Penicillium expansum, and Penicillium oxalicum from the two source environments were compared, revealing modest differences in physiological performance and chemical output. Analysis of LC-MS/MS-derived molecular feature data showed no source-dependent differences in chemical richness. High levels of scaffold homogeneity were also observed with 78-83% of scaffolds shared among the terrestrial and aquatic Penicillium spp. isolates. A comparison of the culturable fungi from the two biomes indicated that certain genera were more strongly associated with aquatic sediments (e.g., Trichoderma, Pseudeurotium, Cladosporium, and Preussia) versus the surrounding terrestrial environment (e.g., Fusarium, Pseudogymnoascus, Humicola, and Acremonium). Taken together, these results suggest that focusing efforts on sampling the microbial resources that are unique to an environment may have a more pronounced effect on enhancing the sought-after natural product diversity needed for chemical discovery and screening collections.

Synthesis Characterization and Biological Evaluation of Nitro Amidinothioureas

Abstract: The discovery of new bioactive compounds necessarily involves previously diversity studies, because by knowing the type of micro organisms that reside in a certain environment, it is possible to design cultivation techniques adapted for all the microbial communities Present in a certain ambience. Marine organisms possess an inexhaustible source of useful chemical substances for the development of new drugs. The structure of the newly synthesized compounds were elucidated with elementary analysis with IR, 1H NMR and mass spectral data. All the synthesized compounds show weak antioxidant activity and weak antimicrobial and antifungal activity against some bacteria and fungi. Keywords: Amidinothiourea, Antibacterial activity and Anti fungal activity.

Development of plant based functional food products: a review

The aging population, the increasing prevalence of lifestyle-related diseases, and the need for improved life status have changed attention from only nutrition to a demanding diet maintaining optimal health, opening export opportunities for countries. In response to this demand, companies are developing technologies for processing novel health and wellness products with a globally expanding market. The development and supply of competitive plant-based functional food products, considering consumers’ needs and market conditions, accompanied by consumer research as a crucial trigger for the development of these products, will continue to be essential. Multidisciplinary action is crucial for the development of innovative and high-quality functional food products compared to conventional foods, focusing on the maintenance of well-being. Innovation and the introduction of products with well-substantiated health claims are also expected, along with evidence to assist consumers in making the right choice of functional food products to achieve the promised health benefits. Furthermore, the validation of health claims, the discovery of new bioactive compounds, and the development of consumer-focused plant-derived functional products all require continued attention.

Endophytic fungi: Benefits for plants and biotechnological potential

Endophytic fungi are microorganisms that live inside plants, establishing a mutualistic relationship, where both benefit from this interaction. They require protection and nutrients from host plants, and in return fungi can contribute to host's growth and nutrient uptake. In addition, they can improve plant tolerance to abiotic and biotic stresses and increase plant resistance to insects and pests. Endophytic fungi produce bioactive compounds similar to those of the host plant. The economic exploitation of these bioactive compounds is much promising. These bioactive products are related to sustainable production systems and to the development of new substances with strong pharmacological properties such as antiviral, antifungal, anti-inflammatory, antitumor and antiparasitic, antidiabetic and immunosuppressant, including response to resistant microorganisms. This study is a descriptive review, having as aim to approach the main benefits of endophytic fungi for host plants, as well as the biotechnological application of the bioactive compounds produced by them. The prospection of endophytic in extreme environment could result in discovery of new bioactive compounds with surprising potential for biotechnology area. So, the development of new research frontiers in this issue is indispensable for the sustainable exploitation of the great benefits that these microorganisms could provide to the science.

A Brief Review of Machine Learning-Based Bioactive Compound Research

Bioactive compounds are often used as initial substances for many therapeutic agents. In recent years, both theoretical and practical innovations in hardware-assisted and fast-evolving machine learning (ML) have made it possible to identify desired bioactive compounds in chemical spaces, such as those in natural products (NPs). This review introduces how machine learning approaches can be used for the identification and evaluation of bioactive compounds. It also provides an overview of recent research trends in machine learning-based prediction and the evaluation of bioactive compounds by listing real-world examples along with various input data. In addition, several ML-based approaches to identify specific bioactive compounds for cardiovascular and metabolic diseases are described. Overall, these approaches are important for the discovery of novel bioactive compounds and provide new insights into the machine learning basis for various traditional applications of bioactive compound-related research.

Study on phytochemical and pharmacological activities of four Rhododendron plants endemic to Northeast China

Rhododendron micranthum Turcz., Rhododendron capitatum Maxim., Rhododendron dauricum L. and Rhododendron schlippenbachii Maxim. are four species of Rhododendron with the same geographical distribution, mainly distributed in the northeast of China and abundant in sources. This paper is the first comprehensive review on the chemical composition and pharmacological activities of these four species. The review, showed 323 compounds including terpenoids, flavonoids, coumarins, lignans, and volatile components were found in the four plants, and these four plants of Rhododendron not only had many chemical constituents of novel structures but also possessed extensive pharmacological effects, such as insecticide, analgesic, antibacterial, antitumor and so on. These research papers and literatures about the four plants were carried out using resources including classic books about Chinese herbal medicine, Flora Reipublicae Popularis Sinicae, and scientific databases including Web of Science, Sci-Finder, CNKI, Pubmed, etc. In recent years, our research group has engaged in the study of chemical composition and pharmacological activities of Rhododendron plants. The terpenes and volatile components isolated from Rhododendron plants contributed greatly to insecticidal activity. Therefore, it is of great significance to review researches of the four endemic resource-rich Rhododendron plants to help make full use of them especially on plant-derived insecticide. This comprehensive review will be significant for the discovery of new bioactive compounds from the above four endemic plants and will be informative for researchers seeking for new pharmacological activity of the four species. • Four species of Rhododendrons from northeast China. • Main chemical components, pharmacological activities of these four Rhododendrons. • Volatile components (Essential oils) and some special compounds contributed to insecticidal activity. • Terpenes and some monomeric compounds with special chemical groups contributed greatly to the insecticidal. • Insecticidal mechanism, some special proteins especially odor-binding proteins (OBPs) of insect was briefly discussed.

Oceanographic setting influences the prokaryotic community and metabolome in deep-sea sponges

Marine sponges (phylum Porifera) are leading organisms for the discovery of bioactive compounds from nature. Their often rich and species-specific microbiota is hypothesised to be producing many of these compounds. Yet, environmental influences on the sponge-associated microbiota and bioactive compound production remain elusive. Here, we investigated the changes of microbiota and metabolomes in sponges along a depth range of 1232 m. Using 16S rRNA gene amplicon sequencing and untargeted metabolomics, we assessed prokaryotic and chemical diversities in three deep-sea sponge species: Geodia barretti, Stryphnus fortis, and Weberella bursa. Both prokaryotic communities and metabolome varied significantly with depth, which we hypothesized to be the effect of different water masses. Up to 35.5% of microbial ASVs (amplicon sequence variants) showed significant changes with depth while phylum-level composition of host microbiome remained unchanged. The metabolome varied with depth, with relative quantities of known bioactive compounds increasing or decreasing strongly. Other metabolites varying with depth were compatible solutes regulating osmolarity of the cells. Correlations between prokaryotic community and the bioactive compounds in G. barretti suggested members of Acidobacteria, Proteobacteria, Chloroflexi, or an unclassified prokaryote as potential producers.

Microalgae as a potential sustainable solution to environment health

Cyanobacteria such as Spirulina platensis secretes numerous biomolecules while consuming CO2 for photosynthesis which can reduce the environmental pollution as it can also be grown in wastewater. These biomolecules can be further processed in numerous pathways such as feed, fuel, pharmaceuticals, and nutraceuticals. This study aims to screen the potential molecular mechanisms of pigments from cyanobacteria as antidiabetic type-2 candidates through molecular docking. The activities of the test compounds were compared to commercial diabetic drugs, such as acarbose, linagliptin and polydatin. The results indicated that the binding affinity of pheophytin, β-carotene, and phycocyanobilin to α-amylase were 0.4, 2, and 2.6 kcal/mol higher than that of acarbose with α-amylase. Binding affinity between pheophytin, β-carotene, and phycocyanobilin with α-glucosidase were found to be comparable, which resulted 1.2, and 1.6 kcal/mol higher than that of acarbose with α-glucosidase. Meanwhile, binding activity of β-carotene and phycocyanobilin with DPP-IV were 0.5 and 0.3 kcal/mol higher than that of linagliptin with DPP-IV, whereas pheophytin, β-carotene, and phycocyanobilin with Glucose-6-phosphate dehydrogenase (G6PD) were 0.2, 1, and 1.4 kcal/mol higher from that of polydatin with G6PD. Moreover, pheophytin, β-carotene and phycocyanobilin were likely to inhibit α-amylase, α-glucosidase, and DPP-IV competitively, while uncompetitively for G6PD. Thus, the integration of molecular docking and experimental approach, such as in vitro and in vivo studies may greatly improve the discovery of true bioactive compounds in cyanobacteria for type 2 diabetes mellitus drugs and treatments.

Identification of Antimicrobial Compounds in Two Streptomyces sp. Strains Isolated From Beehives.

The World Health Organization warns that the alarming increase in antibiotic resistant bacteria will lead to 2.7 million deaths annually due to the lack of effective antibiotic therapies. Clearly, there is an urgent need for short-term alternatives that help to alleviate these alarming figures. In this respect, the scientific community is exploring neglected ecological niches from which the prototypical antibiotic-producing bacteria Streptomycetes are expected to be present. Recent studies have reported that honeybees and their products carry Streptomyces species that possess strong antibacterial activity. In this study, we have investigated the antibiotic profile of two Streptomycetes strains that were isolated from beehives. One of the isolates is the strain Streptomyces albus AN1, which derives from pollen, and shows potent antimicrobial activity against Candida albicans. The other isolate is the strain Streptomyces griseoaurantiacus AD2, which was isolated from honey, and displays a broad range of antimicrobial activity against different Gram-positive bacteria, including pathogens such as Staphylococcus aureus and Enterococus faecalis. Cultures of S. griseoaurantiacus AD2 have the capacity to produce the antibacterial compounds undecylprodigiosin and manumycin, while those of S. albus AN1 accumulate antifungal compounds such as candicidins and antimycins. Furthermore, genome and dereplication analyses suggest that the number of putative bioactive metabolites produced by AD2 and AN1 is considerably high, including compounds with anti-microbial and anti-cancer properties. Our results postulate that beehives are a promising source for the discovery of novel bioactive compounds that might be of interest to the agri-food sector and healthcare pharmaceuticals.

Mining for Active Molecules in Probiotic Supernatant by Combining Non-Targeted Metabolomics and Immunoregulation Testing.

Chronic respiratory diseases such as asthma are highly prevalent in industrialized countries. As cases are expected to rise, there is a growing demand for alternative therapies. Our recent research on the potential benefits of probiotics suggests that they could prevent and reduce the symptoms of many diseases by modulating the host immune system with secreted metabolites. This article presents the first steps of the research that led us to identify the immunoregulatory bioactivity of the amino acid d-Trp reported in our previous study. Here we analyzed the cell culture metabolic footprinting of 25 commercially available probiotic strains to associate metabolic pathway activity information with their respective immune modulatory activity observed in vitro. Crude probiotic supernatant samples were processed in three different ways prior to untargeted analysis in positive and negative ionization mode by direct infusion ESI-FT-ICR-MS: protein precipitation and solid phase extraction (SPE) using HLB and CN-E sorbent cartridges. The data obtained were submitted to multivariate statistical analyses to distinguish supernatant samples into the bioactive and non-bioactive group. Pathway analysis using discriminant molecular features showed an overrepresentation of the tryptophan metabolic pathway for the bioactive supernatant class, suggesting that molecules taking part in that pathway may be involved in the immunomodulatory activity observed in vitro. This work showcases the potential of metabolomics to drive product development and novel bioactive compound discovery out of complex biological samples in a top-down manner.

Asymmetric construction of densely functionalized three-dimensional aza-tetracyclic scaffolds for drug discovery.

Asymmetric construction of densely functionalized three-dimensional aza-tetracyclic scaffolds were achieved by intramolecular Diels-Alder reaction of bicyclic precursors derived from L-tyrosine. Three substituents were systematically introduced into the developed scaffolds in various combinations, demonstrating their high utility in drug discovery.

CRISPR/Cas-Mediated Genome Editing of Streptomyces.

Streptomyces are an important source and reservoir of natural products with diverse applications in medicine, agriculture, and food. Engineered Streptomyces strains have also proven to be functional chassis for the discovery and production of bioactive compounds and enzymes. However, genetic engineering of Streptomyces is often laborious and time-consuming. Here we describe protocols for CRISPR/Cas-mediated genome editing of Streptomyces. Starting from the design and assembly of all-in-one CRISPR/Cas constructs for efficient double-strand break-mediated genome editing, we also present protocols for intergeneric conjugation, CRISPR/Cas plasmid curing, and validation of edited strains.

Past and future of trypanosomatids high-throughput phenotypic screening.

Diseases caused by trypanosomatid parasites affect millions of people mainly living in developing countries. Novel drugs are highly needed since there are no vaccines and available treatment has several limitations, such as resistance, low efficacy, and high toxicity. The drug discovery process is often analogous to finding a needle in the haystack. In the last decades a so-called rational drug design paradigm, heavily dependent on computational approaches, has promised to deliver new drugs in a more cost-effective way. Paradoxically however, the mainstay of these computational methods is data-driven, meaning they need activity data for new compounds to be generated and available in databases. Therefore, high-throughput screening (HTS) of compounds still is a much-needed exercise in drug discovery to fuel other rational approaches. In trypanosomatids, due to the scarcity of validated molecular targets and biological complexity of these parasites, phenotypic screening has become an essential tool for the discovery of new bioactive compounds. In this article we discuss the perspectives of phenotypic HTS for trypanosomatid drug discovery with emphasis on the role of image-based, high-content methods. We also propose an ideal cascade of assays for the identification of new drug candidates for clinical development using leishmaniasis as an example.

Synthesis and Evaluation of Antibacterial Activity of 1,2,3-Triazole and Ether Derivatives of Paeonol

Multi-drug-resistant bacteria (MDR) are the cause of different infections and diseases that have affected humanity for a long time, and have been an emerging global health problem that has led to increased morbidity and mortality. The growing emergence of MDR bacteria has underlined the need for development and discovery of new antibacterial compounds. In this context, a series of new paeonol 1,2,3-triazole and ether derivatives were synthesized using copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and nucleophilic substitution. Paeonol has been a natural product widely studied due to its many biological activities, as well as its derivatives. Three ether derivatives (two unpublished) and ten triazole derivatives (six unpublished) of paeonol were obtained, which were determined by nuclear magnetic resonance (NMR), Fourier transform infrared spectrometry (FTIR), Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and six of them by X-rays, which is the first study of this type presented for these compounds. All the synthesized compounds were evaluated as antibacterial agents against Staphylococcus aureus and Escherichia coli, obtaining a minimum inhibitory concentration (MIC) above 100 µg mL-1. The results showed that CuAAC and nucleophilic substitution were very useful to obtain new paeonol triazole and ether derivatives and the products were obtained in yields from 21.3 to 98.5%. The advantages of these reactions (high yield in most compounds, reaction time, low impurities) show that using the method to produce new derivatives is advisable thus assisting in the discovery of new potential bioactive compounds.

A comprehensive review on chemistry and pharmacology of marine bioactives as antimetastatic agents

Metastasis by and large is responsible for the worldwide deaths associated with various types of cancers. The metastatic variant of cancer cells generated due to the cellular heterogeneity and abnormal activation of various signaling pathways in the tumor population leads to the progressive colonization of cancer cells in various organs. Over the years there has been a constant effort towards developing effective therapeutic strategies for the treatment and prevention of metastasis. The current conventional therapies have lacked efficacy due to the complex nature of metastasis involving multistep processes comprising tumor-tumor and tumor–extracellular matrix adhesion molecules, EMT, proteases, and tumor developing cell pathways. Albeit the exact mechanism of metastasis is somewhat still uncertain, there are a few recognized targets such as EMT markers, MMPs, serine proteases, microtubulin, angiogenic markers, and anoikis resistance, that have been identified as potential therapeutic targets for the inhibition of metastatic progression of cancer cells. Marine biodiversity offers unique chemical compounds due to the exposure to stressful environments for the discovery of novel bioactive compounds that are highly specific to these therapeutic targets. The review discusses various natural and semisynthetic compounds of marine origin having antimetastatic potential, focusing on the isolation, underlying mechanism of inhibition of multiple signaling pathways, and structural modification of isolated compounds for further development as drug candidates having superior clinical translation potential.

Challenges to Explore Genus Streptomyces in Ethiopia-A Mini Review

Genus Streptomyces is gram-positive bacteria that grow in various environments. It has plentiful biotechnological attributes on the area of agricultural, bioremediation, biofuel, clinical, food, industrial, medical, pharmaceutical, and veterinary. The aim of the review is to frontward challenges to explore potent Streptomyces species in the case of Ethiopia. There is lack of the extent and quality of the genetic research regarding to genome sequence, bioactive compound discovery, and genetic manipulation. Their functional and structural diversity is not full studied. To find a new Streptomyces species: Culture media formulation and optimization as wells culture-independent method like Next Generation Sequencing approach should incorporate at national level.

Medicinal plants of Aurora, Zamboanga del Sur, Philippines: Traditional knowledge and use amongst healers and locals

Health care quality and services can be significantly improved through the involvement of grassroots communities. In the Philippines, herbal medicines have been integrated into mainstream clinical practice to improve the healthcare system. However, knowledge of ethnopharmacology in the country is still limited, especially in rural areas like Aurora in Zamboanga del Sur— a municipality with a long history of herbal medicine usage. This study aims to document folk healing practices, utilization, and knowledge of medicinal plants and to quantitatively evaluate ethnopharmacological data from the area. This study documented 165 ethnomedicinal plant species from 64 families, categorized into 16 use categories. We found differences in medicinal plant knowledge based on age, social status, and occupation but not gender. Ethnopharmacological utilization of plants among informants was in strong agreement, with the highest number of species (71) used to treat digestive problems. Several interesting features of local folk medicine were noted, including tuga (healing power bestowed by gods and spirits) and himulso (pulse analysis). Concepts of people–plant interactions and the doctrine of signatures were also observed. Several plant species identified in this study remain understudied; thus, our documentation provides a starting point for the discovery of novel bioactive compounds while promoting pharmacovigilance. This study will also serve as a reference for establishing better management and conservation strategies of floral resources and culture in the area.