Synthetic Compounds Research Articles

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.

“The mushroom was more alive and vibrant”: Patient reports of synthetic versus organic forms of psilocybin

AbstractInterest in psychedelic research in the West is surging, however, clinical trials have almost exclusively studied synthetic compounds such as MDMA, ketamine, DMT, LSD, ibogaine, and psilocybin. To date, few clinical trials have utilized whole mushroom/plant material like Psilocybe mushrooms, Iboga, or Ayahuasca. Individuals participating in the Roots To Thrive Psilocybin-Assisted Therapy for End of Life Distress program were administered synthetic psilocybin, whole Psilocybe cubensis, and mycological extract on separate occasions and post-treatment interview transcripts were qualitatively analyzed to discern themes and patterns. There was broad consensus that all three forms were helpful and similar, all generating visual and perceptual distortions, emotional and cognitive insight, and mystical experiences. However, synthetic psilocybin was said to feel less natural compared to organic forms, and the overall quality of experience of synthetic psilocybin was inferior to the organic forms. Research should be conducted with whole psychedelic mushrooms and extract in addition to synthetic psilocybin given this preliminary data, especially when considering that medicine keepers around the world have utilized whole mushrooms and plant material for millennia.

Interaction of 4-ethyl phenyl sulfate with bovine serum albumin: Experimental and molecular docking studies.

4-ethyl phenyl sulfate (EPS), a protein-bound uremic toxin found in serum of patients suffering from autism spectrum disorders (ASD) and chronic kidney disease (CKD). As per recent advances in the field, gut metabolites after their formation goes to blood stream crosses blood brain barrier and causes neuro related problems. Increased levels of 4-EPS in human body causes anxiety in patients and its role remains elusive. 4-EPS interacts with serum albumin in human body and thus, a model study of interaction of BSA with 4-EPS is presented in support of it. Absorption spectroscopy result demonstrated decrease in bovine serum albumin (BSA) absorption upon interaction with increasing concentration of EPS in a range from 2 μM to 100 μM. Moreover, this interaction was confirmed by the fluorescence quenching in presence of metabolite. The change in secondary structure was demonstrated by circular dichroism, synchronous fluorescence and Fourier transform infra-red spectroscopy. Docking studies reveals binding score of -5.28 Kcal mol-1, demarking that 4-EPS is involved in interaction with BSA via amino acid residues, forming the stable complex. This interaction study may be helpful in devising strategies for the treatment of chronic kidney disease and other neuro related diseases, by producing synthetic compound that competes with albumin binding sites to allow 4-EPS clearance from the body.

Adsorptive Removal of Dyes: A Comparison of Graphene Oxide to Granular Activated Carbon and Zeolite NaY

Synthetic carbon-based compounds are a prevalent wastewater contaminant that can adversely impact water resources due to their potential carcinogenic and toxic effects on aquatic biota and human health. This research investigates the versatility of graphene oxide (GO) as an alternative to commonly used adsorbents (zeolite NaY (NaY) and granular activated carbon (GAC)) for removal of synthetic cationic dyes. Rhodamine B (RhB) and methylene blue (MB), were selected as the target contaminants to represent cationic synthetic dyes with differing molecular sizes and structural compositions. Batch experiments using GO, NaY, and GAC as adsorbents were used to assess both physicochemical interactions between adsorbent surfaces and contaminants, and removal efficiency. GO demonstrated the highest removal efficiency for both target contaminants—at 99% and 86%, respectively—while the lowest removal efficiency was observed for NaY. Langmuir, Freundlich, Temkin, and BET isotherm models were used to describe the adsorption isotherms. Overall, GO demonstrated a more robust and higher removal efficiency of cationic dyes compared with GAC and NaY, indicating the potential of graphene oxide for the removal of complex structured organic contaminants in wastewater treatment.

Time-Dependent Comparison of the Structural Variations of Natural Products and Synthetic Compounds.

The identification of natural products (NPs) has played a pivotal role in drug discovery and shaped the evolution of synthetic compounds (SCs). However, the extent to which NPs have historically influenced the structural characteristics of SCs remains unclear. In this study, we conducted a comprehensive, time-dependent chemoinformatic analysis to investigate the impact of NPs on the structural evolution of SCs. The physicochemical properties, molecular fragments, biological relevance, and chemical space of the molecules from the Dictionary of Natural Products were compared in a time series fashion with a synthetic compound collection sourced from 12 databases. Our findings reveal that NPs have become larger, more complex, and more hydrophobic over time, exhibiting increased structural diversity and uniqueness. Conversely, SCs exhibit a continuous shift in physicochemical properties, yet these changes are constrained within a defined range governed by drug-like constraints. SCs possess a broader range of synthetic pathways and structural diversity, albeit with a decline in biological relevance. The chemical space of NPs has become less concentrated compared to that of SCs. In conclusion, our study suggests that the structural evolution of SCs is influenced by NPs to some extent; however, SCs have not fully evolved in the direction of NPs.

The ENDOMIX perspective: how everyday chemical mixtures impact human health and reproduction by targeting the immune system†.

Endocrine disruptor chemicals (EDCs) are natural and synthetic compounds found ubiquitously in the environment that interfere with the hormonal-immune axis, potentially impacting human health and reproduction. Exposure to EDCs has been associated with numerous health risks, such as neurodevelopmental disorders, metabolic syndrome, thyroid dysfunction, infertility, and cancers. Nevertheless, the current approach to establishing causality between EDCs and disease outcomes has limitations. Epidemiological and experimental research on EDCs faces challenges in accurately assessing chemical exposure and interpreting non-monotonic dose response curves. In addition, most studies have focused on single chemicals or simple mixtures, overlooking complex real-life exposures and EDC mechanistic insights, in particular regarding their impact on the immune system. The ENDOMIX project, funded by the EU's Horizon Health Program, addresses these challenges by integrating epidemiological, risk assessment, and immunotoxicology methodologies. This systemic approach comprises the triangulation of human cohort, in vitro, and in vivo data to determine the combined effects of EDC mixtures. The present review presents and discusses current literature regarding human reproduction in the context of immunotolerance and EDC mode of action. It further underscores the ENDOMIX perspective to elucidate the impact of EDCs on immune-reproductive health.

Potato β-aminobutyric acid receptor IBI1 manipulates VOZ1 and VOZ2 transcription factor activity to promote disease resistance.

Upon infection with non-pathogenic microorganisms or treatment with natural or synthetic compounds, plants exhibit a more rapid and potent response to both biotic and abiotic stresses. However, the molecular mechanisms behind this phenomenon, known as defense priming, are poorly understood. β-aminobutyric acid (BABA) is an endogenous stress metabolite that enhances plant tolerance to various abiotic stresses and primes plant defense responses, providing the ability to resist a variety of pathogens (broad-spectrum resistance). In this study, we identified an aspartyl-tRNA synthetase (AspRS), StIBI1 (named after Arabidopsis IMPAIRED IN BABA-INDUCED IMMUNITY 1; IBI1), as a BABA receptor in Solanum tuberosum. We elucidated the regulatory mechanisms by which StIBI1 interacts with two NAC (NAM, ATAF1, 2, and CUC2) transcription factors (TFs), StVOZ1 and StVOZ2 (VASCULAR PLANT ONE ZINC FINGER, VOZ), to activate BABA-induced resistance (BABA-IR). StVOZ1 represses, whereas StVOZ2 promotes, immunity to the late blight pathogen Phytophthora infestans. Interestingly, BABA and StIBI1 influence StVOZ1- and StVOZ2-mediated immunity. StIBI1 interacts with StVOZ1 and StVOZ2 in the cytoplasm, reducing the nuclear accumulation of StVOZ1 and promoting the nuclear accumulation of StVOZ2. Our findings indicate that StVOZ1 and StVOZ2 finely regulate potato resistance to late blight through distinct signaling pathways. In summary, our study provides insights into the interaction between the potato BABA receptor StIBI1 and the TFs StVOZ1 and StVOZ2, which affects StVOZ1 and StVOZ2stability and nuclear accumulation to regulate late blight resistance during BABA-IR. This research advances our understanding of the primary mechanisms of BABA-IR in potato and contributes to a theoretical basis for the prevention and control of potato late blight using BABA-IR.

Synthetic free fatty acid receptor (FFAR) 2 agonist 4-CMTB and FFAR4 agonist GSK13764 inhibit colon cancer cell growth and migration and regulate FFARs expression in in vitro and in vivo models of colorectal cancer.

Free fatty acid receptors (FFARs) are G protein-coupled receptors that divide into 4 subtypes; FFAR2 and FFAR3 are activated by short-chain fatty acids, while FFAR1 and FFAR4 - by long-chain fatty acids. Recent studies show the potential involvement of FFARs in the pathophysiology of colorectal cancer (CRC). A decrease in FFAR2 and FFAR4 gene expression is observed in patients with CRC. The aim of our study was to evaluate the anti-cancer effect of FFAR2 and FFAR4 stimulation by selective synthetic agonists in in vitro and in vivo models of CRC. FFAR2 agonist, 4-CMTB, and FFAR4 agonist, GSK137647 were used. Cell viability (CCD 841 CoN and SW-480) was determined after 48h incubation with tested compounds using MTT assay. Real-time qPCR and Western Blot were used to identify changes in FFARs expression. Migration and invasion were characterized by commercially available tests. Colitis-associated CRC (CACRC) mouse model was induced by azoxymethane and dextran sodium sulfate. 4-CMTB and GSK137647 significantly reduced cancer cell growth as well as migration and invasion capacities. Both synthetic compounds increased FFAR2 and FFAR4 expression in SW-480 cells. Neither 4-CMTB nor GSK137647 influenced the course of AOM/DSS-induced CACRC in mice, however, 4-CMTB elevated FFAR2 protein expression in mouse tissues. We presented that stimulation of FFAR2 and FFAR4 may inhibit CRC cell viability and migration and that the FFAR2 and FFAR4 expression decreased in CRC can be restored by treatment with respective agonists, indicating new promising pharmacological targets in CRC treatment.

Modulation of NRF2/KEAP1 Signaling by Phytotherapeutics in Periodontitis.

Periodontitis affects up to 40% of adults over 60 years old and is a consequence of gingivitis. Periodontitis is characterized by a chronic inflammation, periodontal damage, and alveolar bone resorption. The nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2)/Kelch-like ECH-Associated Protein 1 (KEAP1) (NRF2/KEAP1) signaling pathway plays a key role in periodontitis by modulating redox balance and inflammation of the periodontium. However, NRF2 expression is decreased in gingival tissues of patients with periodontitis while oxidative stress is significantly increased in this pathology. Oxidative stress and lipopolysaccharide (LPS) produced by gram-negative bacteria favor the production of inflammatory causing periodontal inflammation and favoring alveolar bone. In this review, we analyzed the current literature regarding the role of natural and synthetic compounds in modulating the NRF2/KEAP1 pathway in in vitro and in vivo models of periodontitis in order to evaluate new potential treatments of periodontitis that can improve the outcome of this disease.

Oral Administration of a Novel, Synthetic Ketogenic Compound Elevates Blood β-Hydroxybutyrate Levels in Mice in Both Fasted and Fed Conditions.

Elevating ketone levels with therapeutic nutritional ketosis can help to metabolically manage disease processes associated with epilepsy, diabetes, obesity, cancer, and neurodegenerative disease. Nutritional ketosis can be achieved with various dieting strategies such as the classical ketogenic diet, the modified Atkins diet, caloric restriction, periodic fasting, or the consumption of exogenous ketogenic supplements such as medium-chain triglycerides (MCTs). However, these various strategies can be unpleasant and difficult to follow, so that achieving and sustaining nutritional ketosis can be a major challenge. Thus, investigators continue to explore the science and applications of exogenous ketone supplementation as a means to further augment the therapeutic efficacy of this metabolic therapy. Here, we describe a structurally new synthetic triglyceride, glycerol tri-acetoacetate (Gly-3AcAc), that we prepared from glycerol and an acetoacetate precursor that produces hyperketonemia in the therapeutic range (2-3 mM) when administered to mice under both fasting and non-fasting conditions. Animal studies were undertaken to evaluate the potential effects of eliciting a ketogenic response systemically. Acute effects (24 h or less) were determined in male VM/Dk mice in both fasted and unfasted dietary states. Concentration levels of β-hydroxybutyrate in blood were elevated (βHB; 2-3 mM) under both conditions. Levels of glucose were reduced only in the fasted state. No detrimental side effects were observed. Pending further study, this novel compound could potentially add to the repertoire of methods for inducing therapeutic nutritional ketosis.

Total synthesis, stereochemical assignment, and biological evaluation of opantimycin A and analogues thereof.

Opantimycin A, a rare antimycin-class antibiotic without the macrolide core, was isolated from Streptomyces sp. RK88-1355 in 2017. In this study, we explored the total synthesis and stereochemical assignment of opantimycin A. The synthesis of all potential diastereomers has been accomplished via traceless Staudinger ligation. A comparison of the spectroscopic data of the synthesized compounds with that reported for the natural product confirmed that the absolute configuration of the natural product was (14S,17R,21R). Two analogous compounds were prepared, where the Dhb ((Z)-dehydrobutyrine) moiety was replaced with Dha (dehydroalanine) or ΔVal moieties, respectively. The inhibitory activities of these synthetic compounds against the production of the anti-inflammatory cytokine IL-6 were evaluated, and two potential candidates for further development as anti-inflammatory agents were identified.

A novel synthetic compound, deferiprone–resveratrol hybrid (DFP-RVT), promotes hepatoprotective effects and ameliorates iron-induced oxidative stress in iron-overloaded β-thalassemic mice

A high amount of iron in β-thalassemia patients can lead to oxidative stress and organ dysfunction, especially liver, the main iron accumulated organ. Iron catabolism causes the generation of reactive oxygen species (ROS), triggering liver inflammation, fibrosis, and cirrhosis. Deferiprone-resveratrol hybrid (DFP-RVT) is chemically synthesized by combining deferiprone (DFP) and resveratrol (RVT) which shows an iron-chelating property along with antioxidant activity. This study explored the hepatoprotective effect of DFP-RVT in iron overloaded β-knockout (BKO) thalassemic mice. The results revealed that DFP-RVT treatment improved liver function in iron-overloaded BKO mice by reducing liver enzymes and increasing hepcidin levels compared to iron overload control mice. Both DFP alone and DFP-RVT treatment groups demonstrated iron chelation effects by decreasing liver iron content (LIC), iron profiles, and iron deposition in the liver. Moreover, DFP-RVT powerfully showed antioxidant properties by decreasing liver and plasma thiobarbituric acid reactive substances (TBARs) and increasing reduced glutathione (GSH) and superoxide dismutase (SOD). Interestingly, transforming growth factor β1 (TGFβ1), which can contribute to chronic liver disease through liver injury, inflammation, fibrosis, and cirrhosis, is highly expressed in iron-overloaded mice. However, both DFP and DFP-RVT treatment significantly reduced TGFβ1 levels compared to the iron-overloaded group. Therefore, DFP-RVT could be a potent hepatoprotective compound through the mobilization of iron, reduction of ROS, improvement of liver enzymes, and alleviation of liver damage, potentially relieving liver dysfunction in iron-overloaded BKO mice.

Cleavage of a Peroxide Bond via a Dual Attack by FunctionalMimics of Glutathione Peroxidase.

Nonmetal-containing peroxidase enzymes, including glutathione peroxidase (GPx), and peroxiredoxins, control cellular redox levels by catalyzing the reduction of H2O2. The remarkably higher reactivity of GPx enzyme as compared to the fully dissociated synthetic selenolate/thiolate molecule is probably due to the dual-attack on the peroxide bond (HO1-O2H) by the enzyme; The first one is a nucleophilic attack of the selenolate/thiolate moiety to O1 atom and the second attack at the O2 atom of the peroxide bond by the acidic "parked proton" from Trp or His residue present at the enzyme's active site, leading to the facile cleavage of O-O bond. Herein, we report two synthetic compounds (1 and 2), having a selenolate (Se-) and a proton donor (imidazolium or -COOH group) moieties, which showed excellent GPx-like activity via dual-attack on the peroxide bond. The combined effect of selenolate moiety that donates electrons to the antibondingorbital of O1-O2 bond and the imidazolium or carboxylic acid moiety at the side chain that forms a strong H-bonding with the O2 atom facilitates O-O bond cleavage of H2O2 more efficiently. 1 and 2 exhibit remarkable ability in protecting Cu(I)-complex [TpmCu(CH3CN)]+ (9) against H2O2 by acting as a sacrificial antioxidant, thereby preventing metal-mediated ROS production.

Computational Approach to Identifying New Chemical Entities as Elastase Inhibitors with Potential Antiaging Effects.

In the aging process, skin morphology might be affected by wrinkle formation due to the loss of elasticity and resilience of connective tissues linked to the cleavage of elastin by the enzymatic activity of elastase. Little information is available about the structural requirements to efficiently inhibit elastase 1 (EC 3.4.21.36) expressed in skin keratinocytes. In this study, a structure-based approach led to the identification to the pharmacophoric hypotheses that described the main structural requirements for binding to porcine pancreatic elastase as a valuable tool for the development of skin therapeutic agents due to its similarity with human elastase 1. The obtained models were subsequently refined through the application of computational alanine-scanning mutagenesis to evaluate the effect of single residues on the binding affinity and protein stability; in turn, molecular dynamic simulations were carried out; these procedures led to a simplified model bearing few essential features, enabling a reliable collection of chemical features for their interactions with elastase. Then, a virtual screening campaign on the in-house library of synthetic compounds led to the identification of a nonpeptide-based inhibitor (IC50 = 60.4 µM) belonging to the class of N-substituted-1H-benzimidazol-2-yl]thio]acetamides, which might be further exploited to obtain more efficient ligands of elastase for therapeutic applications.

A Comprehensive Review on Insect Repellent Agents: Medicinal Plants and Synthetic Compounds.

Plant-based repellents have been used for generations as personal protection against mosquitoes. Ethnobotanical studies provide valuable knowledge for developing natural prod-ucts. Commercial repellents with plant-based ingredients are popular, but insufficient studies follow Pesticide Evaluation Scheme WHO guidelines. Further standardized studies are needed to evaluate repellent compounds and develop high-repellency and safe products. Essential Oils (EOs) from aromatic plants have gained popularity as low-risk insecticides due to their low toxicity and short environmental persistence. These plant-derived EOs, produced through steam distillation, have repellent, insecticidal, and growth-reducing effects on various insects. They control phytophagous insects, bite flies, and home and garden insects. US registration is the main hurdle for new EOs. This review explores the use of essential oils from plants as a natural repellent, focusing on their effectiveness and synergistic effects. Essential oils are vol-atile mixtures of hydrocarbons with diverse functional groups, and their effectiveness is linked to monoterpenes and sesquiterpenes. Synergistic effects can improve their effectiveness, and the use of other natural products, like vanillin, can increase protection time. Cymbopogon spp., Ocimum spp., and Eucalyptus spp. are among the most promising plant families.

Biological activities of metal complexes with Schiff base

Abstract Schiff bases are a class of synthetic compounds that form when primary amines combine with aldehydes or ketones. These compounds are incredibly important across various fields, such as biology, catalysis, and optics, due to their diverse features. One notable aspect is their ability to form complexes with transition metals, which opens up a wide range of potential uses, particularly in human systems. In the human body, Schiff base metal complexes display a range of biological actions, including antibacterial, antifungal, anticancer, and antimalarial properties. The versatility of Schiff bases in reacting with different transition metals gives these complexes intriguing potential for addressing biological issues and treating diseases. This article explores various examples of Schiff bases, metal complexes, and their associated ligands, highlighting their usefulness in a variety of biological applications. The potential of Schiff base metal complexes as valuable agents in resolving medical difficulties and advancing biomedical research is emphasized.

Synthetic and Natural Inhibitors of Mortalin for Cancer Therapy.

Upregulation of stress chaperone Mortalin has been closely linked to the malignant transformation of cells, tumorigenesis, the progression of tumors to highly aggressive stages, metastasis, drug resistance, and relapse. Various in vitro and in vivo assays have provided evidence of the critical role of Mortalin upregulation in promoting cancer cell characteristics, including proliferation, migration, invasion, and the inhibition of apoptosis, a consistent feature of most cancers. Given its critical role in several steps in oncogenesis and multi-modes of action, Mortalin presents a promising target for cancer therapy. Consequently, Mortalin inhibitors are emerging as potential anti-cancer drugs. In this review, we discuss various inhibitors of Mortalin (peptides, small RNAs, natural and synthetic compounds, and antibodies), elucidating their anti-cancer potentials.

Pseudomonas putida A (ATCC 12633) Produces Polyhydroxyalkanoates as by Products During the Degradation of Synthetic Ammonium Compounds Commonly Found in Wastewater

Pseudomonas putida A (ATCC 12633) Produces Polyhydroxyalkanoates as by Products During the Degradation of Synthetic Ammonium Compounds Commonly Found in Wastewater

Heterocyclic Compounds as Bcr-Abl Tyrosine Kinase Inhibitors Against Chronic Myeloid Leukemia

Abstract: Despite significant progress in oncology therapeutics, cancer remains a leading cause of mortality worldwide. Chronic myeloid leukemia, which accounts for 15% of all adult leukemia cases, is characterized by chromosomal abnormalities involving the fusion of the Bcr and Abl genes to form the Bcr-Abl oncogene. Current drug treatment of the disease involves the use of Bcr-Abl tyrosine kinase inhibitors belonging to the first, second, and third generations. However, the toxicity and resistance associated with the use of imatinib, a first-generation Bcr-Abl inhibitor, in cases where the T315I mutation exists, necessitates the need for new tyrosine kinase inhibitors. This review focuses on recent synthetic compounds that exhibit potential as inhibitors of the Bcr-Abl protein which could be utilized in chemotherapy. Herein, we evaluated and summarized 36 studies published in the last few years that reported on newly synthesized and biologically evaluated novel small molecules with different heterocyclic scaffolds as Bcr-Abl tyrosine kinase inhibitors. The intricacy of the structure of newly synthesized compounds and the fact that each compound contains more than one scaffold makes it difficult to infer the potentially active core or scaffold. However, investigating different combined scaffolds enhances the chance of successfully developing novel drug candidates. Overall, the information provided in this review can be beneficial to researchers with an interest in chronic myeloid leukemia and tyrosine kinase inhibitors.

Constructing porous aromatic frameworks from natural products for organic pollutant capture

Organic micropollutants in water have raised increasing concerns about aquatic ecosystems and human health. Porous aromatic frameworks (PAFs) with highly porosity and good stability are widely used as sewage treatment agents. However, most of the PAFs are constructed by laboratory-synthesized building units, which are much expensive and increase the total cost of PAFs. At the same time, it is also a potential threaten that these synthetic compounds may affect human health and environmental safety. These shortcomings limit the environmental application of PAF materials. In this work, a route that synthesizing a series of PAFs was developed by using polyphenolic natural products as building units. As a prototype, PAF-274 was constructed by resveratrol to give a permanently porous material, and used for extracting bisphenol A from water. PAF-274 possessed specific surface area of 242 m2/g, and dual pore size at 1.6 and 2.7 nm. The maximum adsorption capacity for bisphenol A was 897 mg/g, which exceeded many other adsorbents and retained the high removal efficiency after 10 cycles. A wide range of non-toxic and harmless natural products can be used to construct porous materials. This synthetic method of introducing natural products broadens the selection of building units for PAFs and opens a new way for the design of functional porous materials.