Search

Bicyclo[1.1.0]butanes, as structurally unique compounds with high strain energy and diverse chemical properties, are becoming increasingly popular building blocks in organic and pharmaceutical chemistries. Strain-release transformation of bicyclo[1.1.0]butanes has received great attention from chemists as it is atom- and step-economical, and significant achievements have been made in this field. Visible-light photocatalysis, with its green and sustainable properties, enriches the strain-release strategy through an electron transfer or energy transfer pathway under mild conditions. In this review, we highlight the latest advancements in visible-light-induced strain-release reactions of bicyclobutanes, with a particular focus on the reaction mechanism. Organization of the content follows a subdivision based on reaction and product classes. Advances in obtaining unique chemical architectures continue to be breakthroughs in this fascinating field of research. [ABSTRACT FROM AUTHOR]

The use of highly potent but very toxic antibiotics such as colistin has become inevitable due to the rise of antimicrobial resistance. We aimed for a chemically‐triggered, controlled release of colistin at the infection site to lower its systemic toxicity by harnessing the power of click‐to‐release reactions. Kinetic experiments with nine tetrazines and three dienophiles demonstrated a fast release via an inverse‐electron‐demand Diels–Alder reaction between trans‐cyclooctene (TCO) and the amine‐functionalised tetrazine Tz7. The antibiotic activity of colistin against Escherichia coli was masked by TCO units, but restored upon reaction with d‐Ubi−Tz, a tetrazine functionalised with the bacterial binding peptide d‐Ubi29–41. While standard TCO did not improve toxicity against human proximal tubular kidney HK‐2 cells, the installation of an aspartic acid‐modified TCO masking group reduced the overall charge of the peptide and entry to the kidney cells, thereby dramatically lowering its toxicity. The analog Col−(TCO‐Asp)1 had favourable pharmacokinetic properties in mice and was successfully activated locally in the lung by d‐Ubi−Tz in an in vivo infection model, whereas it remained inactive and non‐harmful without the chemical trigger. This study constitutes the first example of a systemically acting two‐component antibiotic with improved drug tolerability. [ABSTRACT FROM AUTHOR]

Although benzimidazoles are well-recognized compounds in medicinal chemistry, they occur in the natural world primarily as lower ligands of Vitamin B12 and other cobamides. In this study, we present the synthesis of 5-methoxy-6-methylbenzimidazole and 5-hydroxy-6-methylbenzimidazole, and demonstrate their ability to produce functional cobamides and N-1'-α-glycosidic-benzimidazolyl-ribosylphosphate isomers which are putative B12 biosynthesis intermediates. [ABSTRACT FROM AUTHOR]

Purpose Minimally invasive surgery (MIS) with integrated enhanced recovery pathways (ERPs) helps reduce length of stay and improve surgical outcomes. As these procedures have become more prevalent over time, pharmacists are in key positions to manage medications in the perioperative space to help optimize transitions of care and reduce safety events. Here we identify several clinical areas across phases of care for these procedures in which the knowledge and guidance of pharmacists, as members of the interprofessional team, are paramount. Summary Perioperative pharmacy expertise is often required for MIS procedures in the areas of acid suppression, antithrombotic management, blood glucose control, drug formulation, immunosuppressant optimization, pain mitigation, and postoperative nausea and vomiting prevention and treatment. For each MIS procedure, pharmacists should identify and consider diet and anatomical changes as well as patient- and surgery-specific risk factors. Pharmacists can then utilize their knowledge of the pharmacokinetics and pharmacodynamics of individual medications along with evidence-based medicine to recommend selection of appropriate agents. Conclusion Pharmacist contributions to perioperative medication management for MIS procedures can improve care as surgical patients navigate transitions through the perioperative setting. Pharmacists can further incorporate medication expertise through development and implementation of institutional MIS protocols within the context of ERPs. As such, any pharmacist should feel empowered to aid in the care of surgical patients. [ABSTRACT FROM AUTHOR]

Target-first drug discovery relies heavily on protein structure information, which severely limits its application. In recent years, fragment-based drug Design (FBDD) has been identified as an alternative solution, where screening of smaller molecules for lower affinity allowed the use of focused libraries with a higher hit rate. It is shown that coupling an sp2-rich heteroaromatic group with a monofunctional sp3-rich core gives fragments (186 examples) with advantageous physical-chemical properties, covering a chemical space often neglected in traditional libraries. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests muscarinic acetylcholine receptors represent novel targets to treat alcohol use disorder. In this review, we draw from literature across medicinal chemistry, molecular biology, addiction and learning/cognition fields to interrogate the proposition for muscarinic receptor ligands in treating various aspects of alcohol use disorder, including cognitive dysfunction, motivation to consume alcohol and relapse. In support of this proposition, we describe cholinergic dysfunction in the pathophysiology of alcohol use disorder at a network level, including alcohol‐induced adaptations present in both human post‐mortem brains and reverse‐translated rodent models. Preclinical behavioural pharmacology implicates specific muscarinic receptors, in particular, M4 and M5 receptors, as potential therapeutic targets worthy of further interrogation. We detail how these receptors can be selectively targeted in vivo by the use of subtype‐selective allosteric modulators, a strategy that overcomes the issue of targeting a highly conserved orthosteric site bound by acetylcholine. Finally, we highlight the intense pharma interest in allosteric modulators of muscarinic receptors for other indications that provide an opportunity for repurposing into the alcohol use disorder space and provide some currently unanswered questions as a roadmap for future investigation. [ABSTRACT FROM AUTHOR]

Discovery of novel antimicrobial drugs is one of the hottest topics in the field of medicinal chemistry. An efficient and catalyst free synthesis of novel fluorinated 5‐substituted 1,2,4‐oxadiazole‐3‐yl benzoxazole derivatives is described. A series of novel compounds have been synthesized and characterized by different spectroscopic techniques such as FTIR, 1H NMR, 13C NMR, and LCMS. When tested for antibacterial activity, the synthesized benzoxazole derivatives exhibited outstanding to good activities in comparison to the conventional medications. Moreover, the theoretical forecasts grounded in molecular docking against microbial DNA gyrase may offer a glimpse into the conceivable mode of operation and establish a connection between the detected antimicrobial efficacy and the binding affinity, illuminating particular thermodynamic (bonded and nonbonded) interactions that regulate the activity. The produced compounds also exhibited promising qualities to develop into viable oral medication candidates when their absorption, distribution, metabolism, and excretion were examined. In summary, the research proposes that these novel compounds have emerged as interesting contender for the development of next generation antimicrobial drugs. Our protocol demonstrates broad substrate scope, dramatic decrease of synthesis time, and energy consumption with excellent yields. [ABSTRACT FROM AUTHOR]

Biological applications of sumanene buckybowl molecule have been widely discussed over the years yet remain still unexplored experimentally. On the other hand, creating cyclodextrin-containing supramolecular assemblies was demonstrated to be a powerful tool in terms of designing effective systems for medicinal chemistry purposes. Here, we show that sumanene molecule exclusively forms 1:1 host-guest complexes with γ-cyclodextrin (γCD) or (2-hydroxypropyl)-γ-cyclodextrin (HP-γCD), as revealed by extensive spectroscopic studies supported with density functional theory (DFT) computations. Based on our preliminary biological studies, we discovered that the formation of such complexes resulted in the improvement of anticancer properties of sumanene, expressed by high cell viabilities in vitro of healthy human mammary fibroblasts (HMF) together with low viabilities of human breast adenocarcinoma cells (MDA-MB-231). Improved pharmacokinetic (ADME-Tox) properties for sumanene@γCD and sumanene@HP-γCD complexes in comparison to native sumanene were also supported by in sillico modeling studies. This work provides the method how to focus the cytotoxic action of sumanene toward cancer cells using supramolecular assembly strategy, paving the way to the further exploration of biological properties of sumanene-containing supramolecular systems with bioactive features and applications of this buckybowl in general. [ABSTRACT FROM AUTHOR]

Comprehensive Summary Alkenylsulfonates are commonly encountered in medicinal chemistry, polymer chemistry, and organic synthesis. In this research, an electrochemical reaction involving alkynes, NaHSO3, and alcohols has been developed. This method yields functionalized alkenylsulfonates in good yields with broad functional group tolerance. Mechanism studies indicate that anodic oxidation of inorganic sulfite, radical insertion process, and HAT process are involved in this transformation. [ABSTRACT FROM AUTHOR]

A strategy for the photosensitized [2+2]‐cycloaddition between styrenyl dihaloboranes and unactivated allylamines to access cyclobutylboronates with control of stereochemistry and regiochemistry is presented. The success of the reaction relies on the temporary coordination between in situ generated dihaloboranes and amines under mild reaction conditions. In addition, cyclobutanes with varying substitution patterns have been prepared using N‐heterocycles as directing group. Manipulation of the C−B bond allows for the synthesis of a diverse class of cyclobutanes from simple precursors. Moreover, these reactions lead to the synthesis of complex amines and heteroaromatic compounds, which have significant utility in medicinal chemistry. Finally, a dearomative [4+2]‐cycloaddition of naphthalenes using a boron‐enabled temporary tethering strategy has also been uncovered to synthesize complex 3‐dimensional borylated building blocks. [ABSTRACT FROM AUTHOR]

Deuterium-labeled molecules play a crucial role in numerous areas, from medicinal chemistry to chemical biology, providing a unique opportunity to improve ADMET properties and study the biological fate of bioactive molecules. Herein, we present an electromigratory reductive deuteration of terminal alkynes to access a diverse array of enamides with more than 3 deuteriums incorporated per molecule, using CD3CN as a deuterium source. The reaction proceeds under mild neutral conditions, does not require precious transition metals, and shows broad substrate scope with excellent E-selectivity. We envision that this on-demand high deuterium incorporation will provide considerable opportunities in therapeutics and biological research. [ABSTRACT FROM AUTHOR]

Background: Fatigue is a prevalent issue that can lead individuals to a sub-health condition, impacting their work efficiency and quality of life. There are limited effective treatment options available for fatigue. Ren-Shen-Bu-Qi decoction (RSBQD) is a proprietary herbal remedy that is designed to address fatigue. However, the specific pharmacological mechanisms and basis of RSBQD are not yet fully understood. Purpose: This study aimed to investigate the pharmacological effects and mechanisms of RSBQD in a mouse model of exercise fatigue. Materials and methods: UPLC-Q-Orbitrap HRMS was used to analyze the chemical composition of RSBQD. The pharmacological basis and molecular mechanism of RSBQD on exercise fatigue were predicted using network pharmacology analysis. Subsequently, an exercise fatigue mouse model was established and used to analysis the effects of RSBQD. The potential mechanisms were verified by hematoxylin–eosin (HE) staining, real-time fluorescence quantitative PCR (RT-qPCR), Western blot (WB) and molecular docking. Results: The results showed that 88 main components of RSBQD were identified, which have mainly belonged to flavonoids and carboxylic acid compounds. The network pharmacology analysis indicated that RSBQD ameliorate fatigue through PI3K/AKT signaling pathway. Notably, RSBQD prolonged the swimming time and diminished body weight loss of exercise fatigue mice (P < 0.05). Meanwhile, RSBQD significantly alleviated the injury of liver and kidney induced by exhaustive exercise, and decreasing the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea and BUN levels (P < 0.05). In addition, RSBQD was found could relieve exercise fatigue by decreasing the content of creatine kinase (CK), lactate dehydrogenase (LDH), and lactic acid (LA), but increasing the blood glucose (GLU) and liver glycogen (HG) levels (P < 0.05). RSBQD also significantly increased the hepatic superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) but decreased hepatic malondialdehyde (MDA) levels. Moreover, RSBQD was able to upregulate protein level of activated Nrf2 and PI3K/AKT signaling pathways. Conclusions: RSBQD mitigates exercise fatigue by reversing metabolic changes and reducing oxidative damage through the PI3K/AKT/Nrf2 signaling pathway. This study offers pharmacological support for the utilization of RSBQD in exercise fatigue treatment. [ABSTRACT FROM AUTHOR]

Reversible covalent electrophiles with the advantages of both reversible and covalent interactions receive much attention in the fields of chemical biology and medicinal chemistry. Here, we report two electron-deficient olefins activated by amide and ester, amide-substituted acrylamide and methyl ester-substituted acrylamide, targeting thiols in a reversible covalent manner. [ABSTRACT FROM AUTHOR]

Chiral organofluorine compounds featuring a monofluoromethyl (CH2F)-substituted stereocenter are often encountered in a number of drugs and bioactive molecules. Consequently, the development of catalytic asymmetric methods for the enantioselective construction of CH2F-substituted stereocenters has made great progress over the past two decades, and a variety of enantioselective transformations have been accordingly established. According to the types of fluorinated reagents or substrates employed, these protocols can be divided into the following major categories: (i) enantioselective ring opening of epoxides or azetidinium salts by fluoride anions; (ii) asymmetric monofluoromethylation with 1-fluorobis(phenylsulfonyl)methane; (iii) asymmetric fluorocyclization of functionalized alkenes with Selectfluor; and (iv) asymmetric transformations involving α-CH2F ketones, α-CH2F alkenes, or other CH2F-containing substrates. This feature article aims to summarize these recent advances and discusses the possible reaction mechanisms, advantages and limitations of each protocol and their applications. Synthetic opportunities still open for further development are illustrated as well. This review article will be an inspiration for researchers engaged in asymmetric catalysis, organofluorine chemistry, and medicinal chemistry. [ABSTRACT FROM AUTHOR]

Imidazo-fused diazaborines, which serve as intermediary structures somewhat alongside benzene and borazine, had been of particular interest to Dewar and Snyder more than 60 years ago. To this end, Dewar utilised his ' π -complex theory'so as to represent 'borazaros'as a 'quadrivalent' species; however, sadly, modern representations have deviated and leapt into 'trivalent' counterparts. Bonding in boron species has never been straightforward, to such an extent that the orthodox 'ethane' like diborane, i.e., H3B–BH3, which conformed to the paradigmatic rules of molecular structure, in particular, hybridisation and electronegativity, was later evolved to a more realistic '3-centre 2-electron' bonding so as to give the lie to the purported diborane structures of X-ray diffractors. Herein 11B NMR together with IR spectroscopy sheds light on the nature of bonding in borazaros, and 'caged' cyclic oxazaborons so as to reinforce, and reinvigorate the old literature, which could be of interest to both the synthetic, and medicinal chemist alike. [ABSTRACT FROM AUTHOR]

The review summarizes all synthetic methodologies for the preparation of chromeno[3,2-c]pyridines and chromeno[3,2-c]quinolines. The proposed approaches are systemized based on ways for the construction of the heterocyclic system. The presence of these compounds in nature and their bioactivity are also discussed. Natural products with an annelated chromeno[3,2-c]pyridine fragment are well-known and a number of alkaloids derived from this system as a key core have been recently isolated. These compounds demonstrate antimicrobial, antivirus, and cytotoxic activities, making chromeno[3,2-c]pyridine structural motifs promising for medicinal chemistry. [ABSTRACT FROM AUTHOR]

Imidazole moiety when fused with other heterocyclic system form numerous compounds with different types of pharmacological and biological activities. In this review, we discussed a comprehensive analysis of the synthetic methodologies and reaction mechanisms for imidazo‐fused heterocyclic molecules. These molecules represent a crucial class of compounds due to their significant applications and versatile chemical reactivity. This article meticulously examined various synthetic routes for the construction of imidazo‐fused heterocycles, ranging from traditional methods to modern approaches such as microwave‐assisted reactions, NPs‐catalyzed reactions, light‐mediated synthesis, electrochemical reactions, and transition metal‐free synthesis routes. By consolidating the current knowledge and highlighting future directions, this review aims to serve as a treasure for research community in the fields of organic chemistry, medicinal chemistry, and material science. [ABSTRACT FROM AUTHOR]

Controlled oxidation of methyl‐ketones to aryl glyoxals using Selenium dioxide and iodine is one of the useful transformation. Regardless the availability of many oxidation reagents, Iodine/DMSO system is very efficient and flexible. This system efficiently allows in situ formation of α‐halo ketones and subsequently transforming them directly to useful products. The Iodine/DMSO system allows the selective CI and CO bond formation, substantially useful for converting them to other bond forming reactions and heterocycles useful in the synthetic and medicinal chemistry. Iodine/DMSO system could be an important alternative strategy due to sustainability, metal‐free conditions, allowing multiple/linear domino reactions. This review will focus on heterocyclic systems smartly developed/manipulated by Wu group from methyl‐ketones. The scope and limitations of this method and selected examples of applications for the synthesis of interesting molecules are discussed herein. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we applied translational informatics for intelligent medicine of acute myeloid leukemia, a type of cancer characterized by disease relapses even after seemingly successful treatments. Treatment failure is associated, at least in part, with the fact that targeting individual proteins often promotes rewiring of relevant networks and re-organization of interactions of, among others, non-targeted proteins to eventually evade single-target therapies. To develop efficient therapies, these dynamics should be taken into account and target whole network modules instead of singleton genes in order to prevent the establishment of compensating signaling circuits. Therefore, we integrated network-based methods, structural pharmacology, and molecular modeling to establish two complementary multitargeting strategies, one in the form of repurposable drug combinations and the other as a de novo synthesized triple-targeting agent. Of note, our study exploits, for the first time, a greedy algorithm to identify optimal combinations of drugs and therapeutic protein targets. Background/Objectives: Acute myeloid leukemia (AML) is characterized by therapeutic failure and long-term risk for disease relapses. As several therapeutic targets participate in networks, they can rewire to eventually evade single-target drugs. Hence, multi-targeting approaches are considered on the expectation that interference with many different components could synergistically hinder activation of alternative pathways and demolish the network one-off, leading to complete disease remission. Methods: Herein, we established a network-based, computer-aided approach for the rational design of drug combinations and de novo agents that interact with many AML network components simultaneously. Results: A reconstructed AML network guided the selection of suitable protein hubs and corresponding multi-targeting strategies. For proteins responsive to existing drugs, a greedy algorithm identified the minimum amount of compounds targeting the maximum number of hubs. We predicted permissible combinations of amiodarone, artenimol, fostamatinib, ponatinib, procaine, and vismodegib that interfere with 3–8 hubs, and we elucidated the pharmacological mode of action of procaine on DNMT3A. For proteins that do not respond to any approved drugs, namely cyclins A1, D2, and E1, we used structure-based de novo drug design to generate a novel triple-targeting compound of the chemical formula C15H15NO5, with favorable pharmacological and drug-like properties. Conclusions: Overall, by integrating network and structural pharmacology with molecular modeling, we determined two complementary strategies with the potential to annihilate the AML network, one in the form of repurposable drug combinations and the other as a de novo synthesized triple-targeting agent. These target–drug interactions could be prioritized for preclinical and clinical testing toward precision medicine for AML. [ABSTRACT FROM AUTHOR]

Many herbs have been shown to safely and successfully treat hyperlipidemia. However, the molecular mechanisms underlying their treatment remain unclear. In this study, 103 prescriptions for the treatment of hyperlipidemia containing 146 herbs were screened. Cluster analyses identified a core prescription comprising five herbs, namely, Crataegus pinnatifida (Shan Zha), Cassiae semen (Jue Ming Zi), Alisma orientale (Sam.) Juz. (Ze Xie), Salvia miltiorrhiza (Dan Shen), and RadixPolygoni Multiflori (He Shou Wu), in combination for the treatment of hyperlipidemia. Next, 9, 62, 5, 132, and 34 potential targets for each of the core herbs and a total of 512 hyperlipidemia-related protein targets were detected. Finally, 40 targets shared by core herbs and hyperlipidemia were identified. IL6, AKT1, IL1B, PTGS2, VEGFA, PPARG, and NOS3 were the seven proteins that were found to be most important in the treatment of hyperlipidemia. Interestingly, the Kyoto Encyclopedia of Genes and Genomes pathway indicated that these targets were mainly enriched in the lipid and atherosclerosis pathway and the cancer pathway. In addition, core target proteins such as AKT1, PTGS2, and PPARG have been demonstrated to play critical roles in hyperlipidemia and pancreatic cancer. Significant affinity between bioactive chemicals and proteins involved in cancer pathways was found by molecular docking. Molecular docking results showed that AKT1, PTGS2, and PPARG exhibited good binding ability with three bioactive chemicals, including 3-beta-hydroxymethyllenetanshiquinone, danshexinkum d, and physciondiglucoside. The treatment of hyperlipidemia by herbs may be mediated through the modulation of proteins associated with the cancer pathway. This study helps to provide a theoretical basis for future combined therapy for hyperlipidemia and cancer. [ABSTRACT FROM AUTHOR]

Aurantii Fructus (AF) and Aurantii Fructus Immaturus (AFI) are distinct herbs outlined by the Chinese Pharmacopoeia. They are sourced from the same plant but harvested at different times, resulting in differences in efficacy. It is important to avoid mixing them clinically and to distinguish between the two. Furthermore, dissimilar cultivation conditions may cause variability in the quality of herbs, so it is vital to differentiate drugs from dissimilar origins. In this study, two plants, AF and AFI from different provinces, were comparatively analyzed based on High Performance Liquid Chromatography (HPLC) fingerprints and classified using chemometric methods. The results indicate that the two medicines can be clearly distinguished. Also, AF and AFI grown in different locations can be distinguished. Ten chemical markers were screened, and their variations were determined, including eriocitrin, narirutin, naringin, meranzin hydrate, naringenin, hesperidin, nobiletin, tangeretin, neohesperidin, and poncirin. Subsequent network pharmacology correlated the screened chemical components with the biological network of the organism. The material basis of the difference in efficacy of the two homologous herbs was explored from the perspective of changes in chemical composition. This study provides a reference for formulating quality evaluation standards for AF and AFI and lays a foundation for the efficacy-related quality research of the two. [ABSTRACT FROM AUTHOR]

Fubai chrysanthemum is a kind of traditional Chinese medicine, which can be used as a common food, and is commonly used to improve and relieve visual fatigue. However, its pharmacodynamic material basis and action mechanisms in relieving visual fatigue have not been systematically studied. In this article, 11 absorbed ingredients from Fubai chrysanthemum were detected in rat plasma. Then, the target network pharmacology and KEGG pathway analysis were performed. It was found that Fubai chrysanthemum could inhibit various apoptotic cells and reduce oxidative damage of eyes by regulating the apoptosis pathway, thus alleviating visual fatigue. Further in vitro experiments showed that Fubai chrysanthemum could effectively protect against oxidation damage of adult retinal pigment epithelial cells (ARPE-19), retinal ganglion cells (RGC-5), and lens. The results of cell experiments showed that Fubai chrysanthemum could increase the cell activity, GSH content, and SOD content of ARPE-19 and RGC-5 after oxidative injury, while decreasing the IL-18 content. Similarly, in the study of lens transparency, we found that Fubai chrysanthemum could effectively alleviate the oxidative damage degree of the lens, and significantly increase the content of CAT, GSH, and SOD. The above results suggested that Fubai chrysanthemum could play an important role in alleviating visual fatigue through regulating cell apoptosis and antioxidative damage. [ABSTRACT FROM AUTHOR]

The development of pharmaceutical products is the critical bridge that moves a potential new medicine from academic discovery to applied treatment of patients. It translates an idea for a new drug to bench-level research on how it can be manufactured, formulated, characterized and controlled for use in non-clinical and early clinical trials. From pre-clinical R&D discovery work through the commercial launch, substantial R&D CMC data is generated to develop and optimize cGMP manufacturing and testing operations, while also supporting product comparability, elucidating product / impurity structures, assessing critical quality attributes, developing the drug delivery mode, and developing the product formulation for long-term stability. Significant R&D CMC work continues post-approval to support continuous improvement and market expansion of the commercial product. These activities are crucial elements of Product Lifecycle Management, and taken together, they comprise Pharmaceutical Quality or Chemistry, Manufacturing and Controls (CMC). The objective of this paper is to mitigate the regulatory ambiguity of R&D quality systems with practical, risk-based examples and recommendations when conducting supportive CMC studies for biological products. Making sound strategic CMC decisions under any circumstances assumes data from R&D studies are reliable, traceable, and complete. While there are specific regulatory guidelines on phase-appropriate cGMP activities, none exist for quality practices in R&D CMC laboratories conducting non-cGMP studies. Hindsight is not the time to discover that R&D studies lack key elements that would otherwise have allowed the data to be directly presented to regulators, if needed. There is a strong prospective business interest in protecting considerable investments made for CMC R&D studies. Therefore, establishment of a robust and stage-appropriate R&D laboratory quality system is essential for companies seeking to capitalize on prior knowledge, protect investments, and be prepared for accelerated approval pathways. [ABSTRACT FROM AUTHOR]

Inulin, a naturally occurring polysaccharide derived from plants such as chicory root, has emerged as a significant ingredient in pharmaceutical sciences due to its diverse therapeutic and functional properties. This review explores the multifaceted applications of inulin, focusing on its chemical structure, sources, and mechanisms of action. Inulin's role as a prebiotic is highlighted, with particular emphasis on its ability to modulate gut microbiota, enhance gut health, and improve metabolic processes. The review also delves into the therapeutic applications of inulin, including its potential in managing metabolic health issues such as diabetes and lipid metabolism, as well as its immune-modulating properties and benefits in gastrointestinal health. Furthermore, the article examines the incorporation of inulin in drug formulation and delivery systems, discussing its use as a stabilizing agent and its impact on enhancing drug bioavailability. Innovative inulin-based delivery systems, such as nanoparticles and hydrogels, are explored for their potential in controlled release formulations. The efficacy of inulin is supported by a review of clinical studies, underscoring its benefits in managing conditions like diabetes, cardiovascular health, and gastrointestinal disorders. Safety profiles, regulatory aspects, and potential side effects are also addressed. This comprehensive review concludes with insights into future research directions and the challenges associated with the application of inulin in pharmaceutical sciences. [ABSTRACT FROM AUTHOR]

Summary: Identifying dysregulated plasma proteins in osteoporosis (OP) progression offers insights into prevention and treatment. This study found 8 such proteins associated with OP, suggesting them as therapy targets. This discovery may cut drug development costs and improve personalized treatments. Purpose: This study aims to identify potential therapeutic targets for OP using summary data-based Mendelian randomization (SMR) and colocalization analysis methods. Furthermore, we seek to explore the biological significance and pharmacological value of these drug targets. Methods: To identify potential therapeutic targets for OP, we conducted SMR and colocalization analysis. Plasma protein (pQTL, exposure) data were sourced from the study by Ferkingstad et al. (n = 35,559). Summary statistics for bone mineral density (BMD, outcome) were obtained from the GWAS Catalog (n = 56,284). Additionally, we utilized enrichment analysis, protein–protein interaction (PPI) network analysis, drug prediction, and molecular docking to further analyze the biological significance and pharmacological value of these drug targets. Results: In the SMR analysis, while 20 proteins showed significance, only 8 potential drug targets (GCKR, ERBB3, CFHR1, GPN1, SDF2, VTN, BET1L, and SERPING1) received support from colocalization (PP.H4 > 0.8). These proteins are closely associated with immune function in terms of biological significance. Molecular docking also demonstrated favorable binding of drugs to proteins, consistent with existing structural data, further substantiating the pharmacological value of these targets. Conclusions: The study identified 8 potential drug targets for OP. These prospective targets are believed to have a higher chance of success in clinical trials, thus aiding in prioritizing OP drug development and reducing development costs. [ABSTRACT FROM AUTHOR]

Purpose: Drug administration via feeding tubes is considered a process with many uncertainties. This review aimed to give a comprehensive overview of data available on feeding tube application and to carry out risk assessments for drug substances commonly administered to stroke patients. Methods: Drugs frequently administered via feeding tubes were identified through a retrospective analysis of discharge letters from a stroke unit. Physicochemical, pharmacokinetic, and stability properties of these drugs and data on drug-enteral nutrition interactions were systematically searched for in the European Pharmacopoeia, Hagers Handbook of Pharmaceutical Practice, Birchers clinical-pharmacological data compilation, and the Martindale Complete Drug Reference, as well as from databases including DrugBank, DrugDex, PubChem, Google Scholar, and PubMed. Results: Of the drugs most commonly administered via feeding tubes in the present stroke patient cohort, bisoprolol, candesartan, and ramipril could be considered the least critical due to their overall favourable properties. Acetylsalicylic acid, amlodipine, hydrochlorothiazide, omeprazole and esomeprazole, simvastatin, and torasemide pose risks based on pH or light-dependent instability or proposed food effects. The most critical drugs to be administered via feeding tubes are considered to be furosemide, levodopa, and levothyroxine as they show relevant instabilities under administration conditions and substantial food effects; the latter two even possess a narrow therapeutic index. However, little information is available on drug-tube and drug-formula interactions. Conclusion: Feeding tube administration of medications turned out to be a highly complex process with several unmet risks. Therefore, investigations that systematically assess these risk factors using clinically relevant model systems are urgently needed. [ABSTRACT FROM AUTHOR]

Central nervous system diseases pose a significant threat to human health. Clinical observations have demonstrated that celabenzine, the primary active component of the natural plant ginseng, can potentially alleviate cognitive dysfunction in patients with central nervous system disorders. However, the specific mechanisms of its action remain unclear. The PubMed database was used to identify the targets of celabenzine. Subsequently, a Venn diagram of intersecting targets was constructed by utilizing the identified central nervous system injury targets. Additionally, Cytoscape software (version 3.7.2) was used to construct active ingredient-target and Protein-protein interaction networks. The Metascape database was used to perform Gene Ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Molecular docking was performed on active ingredients and target genes. Network pharmacology analysis revealed that celabenzine shares 175 intersecting targets with central nervous system damage, manifesting its effects through PI3K-Akt and MAPK signaling pathways and proteoglycans in the cancer pathway. Celabenzine demonstrates a strong binding affinity with its target gene, RhoA, indicating stable binding. This study was accomplished using network pharmacology and bioinformatics. Our findings suggested that celabenzine shows its protective effects against central nervous system damage by modulating the RhoA gene. [ABSTRACT FROM AUTHOR]

Heart failure is a geriatric syndrome, often accompanied by a high disability rate, complex comorbidities, and a poor prognosis. This study aimed to assess the effect of Astragalus on the vitamin D- fibroblast growth factor 23/fibroblast growth factor receptor 1-KLOTHO axis in elderly heart failure patients using a bioinformatics approach. Thirteen active ingredients and 159 targets were identified based on network pharmacology, and 500 HF targets were obtained using GeneCards database. A predicted target set was established using 22 core targets, and a diagram of the active component-target network was constructed using Cytoscape software (version 3.7.2); a protein-protein interaction network was constructed for analysis, and the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment were analyzed using DAVID software. Bioinformatics analyses revealed that 22 targets were mainly involved in the Ras and PI3K-Akt signaling pathways. Molecular docking for fibroblast growth factor receptor 1 revealed that the active components HMM7 and HMM13 demonstrated better binding stability with the target gene. This study may help explain the molecular mechanism of effects on vitamin D- fibroblast growth factor 23/fibroblast growth factor receptor 1-KLOTHO axis and promote clinical application. [ABSTRACT FROM AUTHOR]

Combinatorial chemistry and drug design have produced more lipophilic, heavier, and less water soluble drugs in recent years. It is more difficult to find the best drug delivery system for them. In this area of technology and drug development, new strategies are applied to develop novel drug moieties and improve their water solubility. One of the main obstacles is the use of poorly water soluble chemicals in formulation. Beta-ionone (β-ionone) is utilised to target many forms of cancer and has been shown to have anticancer potential in recent studies, however it has poor water solubility. The goal of the current study was to enhance the solubility of beta-ionone using various carrier materials like non-ionic water-dispersible surfactant Gelucire® 50/13 (polyoxylglycerides) which self-emulsifies in aqueous media forming a fine micro-dispersion. Another amphiphilic material, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer was used to enhance the solubility of beta-ionone. Further, Hydroxypropyl-β-Cyclodextrin inclusion complex was also prepared and evaluated to check the improvement in the solubility of beta-ionone. Finally, the performance of these carries was checked by developing the pellet formulation. An appropriate formulation offers a method to improve the solubility, dissolution, and bioavailability of β-ionone. When compared to alternative cancer treatment options, this formulation may aid to improve patient compliance and the drug's effectiveness. The pellet formulation developed utilising HP-β-CD has produced outstanding results and may be more stable due to the inclusion-capabilities, complexes. [ABSTRACT FROM AUTHOR]

β-Carboline bearing indole is one of the heterocyclic compounds that play a vital role in medicinal chemistry with various pharmacological effects such as anticancer, anti-acetylcholinesterase, anti-inflammation, antimalarial, antibacterial, anti-diabetic, and antioxidant. Over the last two decades, many studies on the synthesis and biological activity of indole β-carboline compounds have been conducted yet there is no appropriate data summary has been presented. Thus, the goal of this review was to highlight the synthesis pathway and bioactivity of substituted indole β-carboline reported from 2005 to date. In addition, this will encourage further investigation into the synthesis and evaluation of new indole β-carboline, in the hope of contributing to the development of potentially new medications for the treatment of various ailments. [ABSTRACT FROM AUTHOR]

5‐HT1A receptor (5‐HT1A‐R) is a serotoninergic G‐protein coupled receptor subtype which contributes to several physiological processes in both central nervous system and periphery. Despite being the first 5‐HT‐R identified, cloned and studied, it still represents a very attractive target in drug discovery and continues to be the focus of a myriad of drug discovery campaigns due to its involvement in numerous neuropsychiatric disorders. The structure‐activity relationship studies (SAR) performed over the last years have been devoted to three main goals: (i) design and synthesis of 5‐HT1A‐R selective/preferential ligands; (ii) identification of 5‐HT1A‐R biased agonists, differentiating pre‐ versus post‐synaptic agonism and signaling cellular mechanisms; (iii) development of multitarget compounds endowed with well‐defined poly‐pharmacological profiles targeting 5‐HT1A‐R along with other serotonin receptors, serotonin transporter (SERT), D2‐like receptors and/or enzymes, such as acetylcholinesterase and phosphodiesterase, as a promising strategy for the management of complex psychiatric and neurodegenerative disorders. In this review, medicinal chemistry aspects of ligands acting as selective/preferential or multitarget 5‐HT1A‐R agonists and antagonists belonging to different chemotypes and developed in the last 7 years (2017–2023) have been discussed. The development of chemical and pharmacological 5‐HT1A‐R tools for molecular imaging have also been described. Finally, the pharmacological interest of 5‐HT1A‐R and the therapeutic potential of ligands targeting this receptor have been considered. [ABSTRACT FROM AUTHOR]

The development of peptide drugs has made tremendous progress in the past few decades because of the advancements in modification chemistry and analytical technologies. The novel‐designed peptide drugs have been modified through various biochemical methods with improved diagnostic, therapeutic, and drug‐delivery strategies. Researchers found it a helping hand to overcome the inherent limitations of peptides and bring continued advancements in their applications. Furthermore, the emergence of peptide‐drug conjugates (PDCs)—utilizes target‐oriented peptide moieties as a vehicle for cytotoxic payloads via conjugation with cleavable chemical agents, resulting in the key foundation of the new era of targeted peptide drugs. This review summarizes the various classifications of peptide drugs, suitable chemical modification strategies to improve the ADME (adsorption, distribution, metabolism, and excretion) features of peptide drugs, and recent (2015–early 2024) progress/achievements in peptide‐based drug delivery systems as well as their fruitful implication in preclinical and clinical studies. Furthermore, we also summarized the brief description of other types of PDCs, including peptide‐MOF conjugates and peptide‐UCNP conjugates. The principal aim is to provide scattered and diversified knowledge in one place and to help researchers understand the pinching knots in the science of PDC development and progress toward a bright future of novel peptide drugs. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and is a major health threat globally. Its prevalence is forecasted to exponentially increase during the next 30 years due to the global aging population. Currently, approved drugs are merely symptomatic, being ineffective in delaying or blocking the relentless disease advance. Intensive AD research describes this disease as a highly complex multifactorial disease. Disclosure of novel pathological pathways and their interconnections has had a major impact on medicinal chemistry drug development for AD over the last two decades. The complex network of pathological events involved in the onset of the disease has prompted the development of multitarget drugs. These chemical entities combine pharmacological activities toward two or more drug targets of interest. These multitarget‐directed ligands are proposed to modify different nodes in the pathological network aiming to delay or even stop disease progression. Here, we review the multitarget drug development strategy for AD during the last decade. [ABSTRACT FROM AUTHOR]

Objective: To observe the therapeutic effects and underlying mechanism of baicalin against colon cancer. Methods: The effects of baicalin on the proliferation and growth of colon cancer cells MC38 and CT26. WT were observed and predicted potential molecular targets of baicalin for colon cancer therapy were studied by network pharmacology. Furthermore, molecular docking and drug affinity responsive target stability (DARTS) analysis were performed to confirm the interaction between potential targets and baicalin. Finally, the mechanisms predicted by in silico analyses were experimentally verified in-vitro and in-vivo. Results: Baicalin significantly inhibited proliferation, invasion, migration, and induced apoptosis in MC38 and CT26 cells (all P<0.01). Additionally, baicalin caused cell cycle arrest at the S phase, while the G0/G1 phase was detected in the tiny portion of the cells. Subsequent network pharmacology analysis identified 6 therapeutic targets associated with baicalin, which potentially affect various pathways including 39 biological processes and 99 signaling pathways. In addition, molecular docking and DARTS predicted the potential binding of baicalin with cyclin dependent kinase inhibitor 2A (CDKN2A), protein kinase B (AKT), caspase 3, and mitogen-activated protein kinase (MAPK). In vitro, the expressions of CDKN2A, MAPK, and p-AKT were suppressed by baicalin in MC38 and CT26 cells. In vivo, baicalin significantly reduced the tumor size and weight (all P<0.01) in the colon cancer mouse model via inactivating p-AKT, CDKN2A, cyclin dependent kinase 4, cyclin dependent kinase 2, interleukin-1, tumor necrosis factor α, and activating caspase 3 and mouse double minute 2 homolog signaling (all P<0.05). Conclusion: Baicalin suppressed the CDKN2A protein level to prevent colon cancer and could be used as a therapeutic target for colon cancer. [ABSTRACT FROM AUTHOR]

Objective: To explore the specific pharmacological molecular mechanisms of Laoke Formula (LK) on treating advanced non-small cell lung cancer (NSCLC) based on clinical application, network pharmacology and experimental validation. Methods: Kaplan-Meier method and Cox regression analysis were used to evaluate the survival benefit of Chinese medicine (CM) treatment in 296 patients with NSCLC in Tianjin Medical University Cancer Institute and Hospital from January 2011 to December 2015. The compounds of LK were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and the corresponding targets were performed from Swiss Target Prediction. NSCLC-related targets were obtained from Therapeutic Target Database and Comparative Toxicogenomics Database. Key compounds and targets were identified from the compound-target-disease network and protein-protein interaction (PPI) network analysis, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis were used to predict the potential signaling pathways involved in the treatment of advanced NSCLC with LK. The binding affinities between key ingredients and targets were further verified using molecular docking. Finally, A549 cell proliferation and migration assay were used to evaluate the antitumor activity of LK. Western blot was used to further verify the expression of key target proteins related to the predicted pathways. Results: Kaplan-Meier survival analysis showed that the overall survival of the CM group was longer than that of the non-CM group (36 months vs. 26 months), and COX regression analysis showed that LK treatment was an independent favorable prognostic factor (P=0.027). Next, 97 components and 86 potential targets were included in the network pharmacology, KEGG and GO analyses, and the results indicated that LK was associated with proliferation and apoptosis. Moreover, molecular docking revealed a good binding affinity between the key ingredients and targets. In vitro, A549 cell proliferation and migration assay showed that the biological inhibition effect was more obvious with the increase of LK concentration (P<0.05). And decreased expressions of nuclear factor κB1 (NF-κB1), epidermal growth factor receptor (EGFR) and AKT serine/threonine kinase 1 (AKT1) and increased expression of p53 (P<0.05) indicated the inhibitory effect of LK on NSCLC by Western blot. Conclusion: LK inhibits NSCLC by inhibiting EGFR/phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, NFκB signaling pathway and inducing apoptosis, which provides evidence for the therapeutic mechanism of LK to increase overall survival in NSCLC patients. [ABSTRACT FROM AUTHOR]

Background Pisum sativum: (PS) is a universal legume plant utilized for both human and animal consumption, particularly its seeds, known as green peas. The processing of PS in food industries and households produces a significant amount of waste that needs to be valorized. Methods: In this study, the metabolite profiles of the 70% ethanolic extracts of PS wastes, namely peels (PSP) and a combination of leaves and stems (PSLS), were investigated by liquid chromatography-electrospray ionization-quadrupole time-of-flight tandem mass spectrometry (LC-ESI-QTOF-MS/MS) followed by molecular networking. Results: Different classes of metabolites were identified, being flavonoids and their derivatives, along with phenolic acids, the most abundant categories. Additionally, a comprehensive network pharmacology strategy was applied to elucidate potentially active metabolites, key targets, and the pathways involved in cytotoxic activity against breast cancer. This cytotoxic activity was investigated in MCF-7 and MCF-10a cell lines. Results revealed that PSLS extract exhibited a potent cytotoxic activity with a good selectivity index (IC50 = 17.67 and selectivity index of 3.51), compared to the reference drug doxorubicin (IC50 = 2.69 µg/mL and selectivity index of 5.28). Whereas PSP extract appeared to be less potent and selective (IC50 = 32.92 µg/mL and selectivity index of 1.62). A similar performance was also observed for several polyphenolics isolated from the PSLS extract, including methyl cis p-coumarate, trans p-coumaric acid, and liquiritigenin/ 7-methyl liquiritigenin mixture. Methyl cis p-coumarate showed the most potent cytotoxic activity against MCF-7 cell line and the highest selectivity (IC50 = 1.18 µg/mL (6.91 µM) and selectivity index of 27.42). The network pharmacology study revealed that the isolated compounds could interact with several breast cancer-associated protein targets including carbonic anhydrases 1, 2, 4, 9, and 12, as well as aldo-keto reductase family 1 member B1, adenosine A3 receptor, protein tyrosine phosphatase non-receptor type 1, and estrogen receptor 2. Conclusion: The uncovered therapeutic potential of PSLS and its metabolite constituents pave the way for an efficient and mindful PS waste valorization, calling for further in-vitro and in-vivo research. [ABSTRACT FROM AUTHOR]

Organic halogen compounds are cornerstones of applied chemical sciences. Halogen substitution is a smart molecular design strategy adopted to influence reactivity, membrane permeability and receptor interaction. Chiral bioreceptors may restrict the stereochemical requirements in the halo‐ligand design. Straightforward (but expensive) catalyzed stereospecific halogenation has been reported. Historically, PCl5 served access to uncatalyzed stereoselective chlorination although the stereochemical outcomes were influenced by steric parameters. Nonetheless, stereochemical investigation of PCl5 reaction mechanism with carbamoyl (RCONHX) compounds has never been addressed. Herein, we provide the first comprehensive stereochemical mechanistic explanation outlining halogenation of carbamoyl compounds with PCl5; the key regioselectivity‐limiting nitrilimine intermediate (8‐Z.HCl); how substitution pattern influences regioselectivity; why oxadiazole byproduct (P1) is encountered; stereo‐electronic factors influencing the hydrazonoyl chloride (P2) production; and discovery of two stereoselectivity‐limiting parallel mechanisms (stepwise and concerted) of elimination of HCl and POCl3. DFT calculations, synthetic methodology optimization, X‐ray evidence and experimental reaction kinetics study evidence all supported the suggested mechanism proposal (Scheme 2). Finally, we provide mechanism‐inspired future recommendations for directing the reaction stereoselectivity toward elusive and stereochemically inaccessible (E)‐bis‐hydrazonoyl chlorides along with potentially pivotal applications of both (E/Z)‐stereoisomers especially in medicinal chemistry and protein modification. [ABSTRACT FROM AUTHOR]

Selective recognition and sensing of catecholamine-based neurotransmitters by fluorescent synthetic receptors capable of operating in pure water is a central topic of modern supramolecular chemistry that impacts biological and analytical chemistry. Despite advances achieved in the recognition of some neurotransmitters such as dopamine, little effort has been invested in the optical recognition of other neurotransmitters of paramount importance in biochemistry and medicinal chemistry such as the drug L -dihydroxy-phenylalanine (levodopa). Herein, a cationic Cu(II)–terpyridine complex bearing an intramolecular fluorescent quinolinium ring covalently linked to phenylboronic acid (CuL1) was synthesized, structurally described by single-crystal X-ray diffraction and studied in-depth as a fluorescent receptor for neurotransmitters in water. The complex CuL1 was designed to act as a receptor for levodopa through two Lewis acids of different natures (Cu(II) and B atoms) as cooperative binding points. The receptor CuL1 was found to have a strongly acidified –B(OH)2 group (pKa = 6.2) and exceptionally high affinity for levodopa (K = 4.8 × 106 M−1) with selectivity over other related neurotransmitters such as dopamine, epinephrine, norepinephrine and nucleosides in the micromolar concentration range at physiological pH. Such levodopa affinity/selectivity for a boronic acid-based receptor in water is still rare. On the basis of spectroscopic tools (11B NMR, UV-vis, EPR, and fluorescence), high-resolution ESI-MS, crystal structure, and DFT calculations, the interaction mode of CuL1 with levodopa is proposed in a 1 : 1 model using two-point recognition involving a boronate–catechol esterification and a coordination bond Cu(II)–carboxylate. Furthermore, a visual sensing ensemble was constructed using CuL1 and the commercial fluorescent dye eosin Y. Levodopa is efficiently detected by the displacement of the eosin Y bound to the Cu(II)–receptor, monitoring its green emission. The use of Cu(II)–boronate complexes for fast and selective neurotransmitter sensing was unexplored until now. [ABSTRACT FROM AUTHOR]

Organic compounds with potential antioxidant activity have attracted special attention of researchers and they have been widely studied in several areas, including pharmacology and medicinal chemistry. In this context, electrochemistry through cyclic voltammetry becomes a fast and efficient tool for the characterization of the antioxidant potential of these compounds. Herein, a study was carried out on the electrochemical behavior of seleno‐dihydropyrimidinones and chloro‐dihydropyrimidinones via cyclic voltammetry in the presence of acetonitrile. By employing this approach, the characterization of the oxidation processes and the determination of antioxidant activities of the target molecules was disclosed. It was also proposed a comparison of the results obtained with the antioxidant activity of the 2,2‐diphenyl‐1‐picrylhydrazyl radical. Among the evaluated compounds, four molecules exhibited significant antioxidant capacities which were efficiently detected by 2,2‐diphenyl‐1‐picrylhydrazyl radical assay and by cyclic voltammetry when measuring the charges transferred until 0.9 V vs Fc+/Fc. [ABSTRACT FROM AUTHOR]

ABSTRACT 2‐Thioxo‐4‐thiazolidinone which is trivially known as rhodanine is a five‐membered heterocycle, containing a sulfur and nitrogen atom at 1 and 3 positions, respectively. It is a very attractive class of compounds, because derivatization of rhodanine yields a number of molecules having multifarious application in medicinal chemistry and biology. There are many molecules derived from rhodanine which are already being used commercially as drug molecules. So owing to the importance of rhodanine in the field of medicinal chemistry and biology, a comprehensive review familiarizing different derivatives of the parent molecule rhodanine and their syntheses is highly warranted. In this review, we have broadly categorized the reactions of rhodanine as; (a) Knoevenagel condensation through the C‐5 active methylene group with carbonyl compounds, (b) nucleophilic attack on thioxo group at position 2 of rhodanine by aliphatic amines, (c) thioxo to oxo conversion, and (d) all other reactions. So far, to the best of our knowledge, no such literature which accounts for all the different kinds of reactions of rhodanine is reported. Here, we have not only presented the reactions schemes from various literatures, but we have discussed about the advantages and inadequacies of that particular catalytic processes. Moreover, at the end of this article we have given our own critical analysis on these literature reports, based on our understanding and experience. [ABSTRACT FROM AUTHOR]

Objective: Our study focused on the effects and molecular mechanisms of kaempferol, a major active component of Eucommia ulmoides Oliver (EUO), on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Methods: Target molecules for EUO, osteoarthritis, and osteogenic differentiation were identified through network pharmacology analysis. BMSCs were isolated and treated with various concentrations of kaempferol. Optimal concentration was determined through MTT assays. Osteogenic differentiation was assessed using alkaline phosphatase (ALP) and Alizarin Red S staining, while osteogenic markers (Collagen I, RUNX2, and OPN) and CAV-1 expression were analyzed using RT-qPCR and Western blot. The effects of combined treatment with kaempferol and an overexpression vector for CAV-1 (oe-CAV-1) on osteogenic differentiation were also observed. Results: Network pharmacology analysis identified kaempferol as the primary active component influencing CAV-1 targeted in subsequent experiments. It was found that 10 µM kaempferol was optimal for treating BMSCs. Post-treatment, significant increases in ALP activity and calcium deposition were observed, along with elevated expression of osteogenic markers, and decreased CAV-1. Overexpression of CAV-1 significantly reversed the promotive effects of kaempferol on BMSC osteogenic differentiation, effectively inhibiting the process. Conclusion: Collectively, kaempferol promotes osteogenic differentiation in BMSCs by inhibiting CAV-1 expression. [ABSTRACT FROM AUTHOR]

Carbazole derivatives are vital in medicinal and materials chemistry, yet accessing diverse substitutions remains challenging. Here, we introduce a regioselective approach for C1 and C8 alkynylation of carbazoles via palladium‐catalyzed C−H activation. This method provides a direct route to mono‐ and di‐alkynylated derivatives, addressing the scarcity of alkynylated carbazole‐based materials. Our study broadens the synthetic toolbox for carbazole functionalization, offering potential applications in optoelectronics, bio‐imaging, and beyond, while contributing to developing sustainable C−H activation methodologies. [ABSTRACT FROM AUTHOR]

Heterocyclic fluoroalkylation is initiated through a photochemical reaction involving an electron donor–acceptor complex. The reaction proceeds smoothly without requiring a photocatalyst, transition metal catalyst or additional oxidant. Through extensive experiments, we optimised the heterocyclic fluoroalkylation method and confirmed its versatility and effectiveness on various substrates. The process synthesises fluoroalkylated quinoxalinones and indolones with high efficiency and was successfully extended to gram‐scale applications, highlighting its practical utility. Detailed mechanistic analyses, supported by density functional theory calculations elucidated the role of the electron donor–acceptor complexes and deciphered the distinct radical chain reaction mechanism inherent in the halogen‐atom transfer pathway. Given the importance of fluoroalkyl groups in pharmaceuticals, this simple and efficient method promises substantial applications in medicinal chemistry and materials science. [ABSTRACT FROM AUTHOR]

Achieving precise deuterium labeling in pharmaceutical compounds presents a formidable challenge in medicinal chemistry. Herein, we introduce an innovative approach for circumventing the use of costly and environmentally unfriendly photocatalysts, enabling precise decarboxylative deuteration under mild conditions. Mechanistic investigation unveils the dual functionality of the tailored photoredox-active acid (PAC) with a photosensitive amino protecting group, serving both as a reactant and as a catalyst. This methodology not only represents a sustainable solution, eliminating the need for additional transition-metal catalysts, but also showcases exceptional regio- and chemoselectivity, successfully producing a versatile range of deuterated amines and alkanes, including complex peptides, terpenoids, and steroidal natural products. This breakthrough marks a significant advancement in the realm of photoinduced autocatalytic reaction methodologies. [ABSTRACT FROM AUTHOR]

Past decades have witnessed significant advance of isocyanides as a class of versatile organic synthons as well as their broad applications in multi-component reactions (MCRs) and other tandem reactions. Reactions involving multiple isocyanides allow the construction of molecules with further diversification and complexity, while C–H functionalization emphasizes the advantages of high atom economy, broad substrate availability and great synthetic efficiency. This promising synergistic strategy of C–H functionalization involving multiple isocyanides provides a variety of valuable synthetic methods for organic chemists' toolbox and offers considerable potential in pharmaceutical chemistry and materials science as well. The present review outlines in detail various reaction types of C–H functionalization enabled by multiple isocyanides, and the relevant mechanistic rationale is discussed. [ABSTRACT FROM AUTHOR]

8‐Methylquinoline is regarded as an ideal substrate to participate in diversely C(sp3)−H functionalization reactions. The presence of the chelating nitrogen atom enables 8‐methylquinoline to easily form cyclometallated complexes with various transition metals, leading to the selective synthesis of functionalized quinolines. Considering the great importance of quinoline cores in medicinal chemistry, in this review article, we have covered the publications related to the C−H activation and functionalization of 8‐methylquinoline under transition metal catalysis during the last decade. [ABSTRACT FROM AUTHOR]

Both the pyrroloindoline core and N–CF3 moiety hold significant importance in medicinal chemistry. However, to date, no instances of constructing N–CF3-containing pyrroloindolines have been reported. Herein, we present a robust and operationally simple approach to assembling such intriguing skeletons from tryptamine-derived isocyanides through a cascade sequence, which includes an oxidative trifluorination and a subsequent halogenative cyclization. Key to the success lies in the development of a facile conversion of isocyanides to N–CF3 moiety with commercially available reagents N-halosuccinimide and Et3N·HF. The protocol features mild reaction conditions, broad functional group tolerance, good to excellent yields, and high diastereoselectivities. In addition, we demonstrate that the halide substituent within the products serves as a versatile functional handle for accessing diverse C3-quaternary-substituted N–CF3-pyrroloindolines. Both the pyrroloindoline core and N–CF3 moiety hold significant importance in medicinal chemistry. Herein, the authors present a simple approach to assembling such intriguing skeletons from tryptamine-derived isocyanides through a cascade sequence, which includes an oxidative trifluorination and a subsequent halogenative cyclization. [ABSTRACT FROM AUTHOR]

Herein we report the preparation of C4‐functionalized proline‐derived azabicycloalkane (Aba) amino acids by exploiting a direct ring closing enyne metathesis reaction of readily accessible dipeptide precursors. The reverse‐turn inducing properties of the newly synthesized constrained dipeptide mimics were assessed by computational studies. Furthermore, the desired Aba derivatives, carrying a synthetically versatile diene moiety, were subjected to post‐functionalization reactions to validate their potential application in peptide/peptidomimetic chemistry and drug discovery. [ABSTRACT FROM AUTHOR]

ABSTRACT The syntheses and bioevaluation of 3‐acyl‐2‐pyridones have garnered significant interest in recent years as a novel class of compounds with diverse biological activities. The bioactivities cover a wide range of therapeutic areas including antimicrobial, antitumor, anti‐inflammatory, antifungal, antibiotic, neuritogenic, cytotoxic, and antiviral activities. Therefore, 3‐acyl‐2‐pyridone scaffold offers a versatile platform for the development of new molecules with potential applications in medicinal chemistry. The recent exploration on synthesis and bioevaluation of 3‐acyl‐2‐pyridones has yielded promising results, making them attractive targets for further optimization and development of new therapeutic agents. This review summarizes the available information on total synthesis of 3‐acyl‐2‐pyridone containing natural products, and the other synthetic strategies developed for accessing the 3‐acyl pyridones such as multicomponent synthesis, condensation reaction, microwave‐assisted synthesis, catalytic hydrogenation reactions, metalation reaction, Michael addition, and formylation reactions. The presented information may serve as a valuable resource for researchers working in the field of medicinal chemistry and drug discovery, stimulating further exploration and development of this intriguing scaffold. [ABSTRACT FROM AUTHOR]

Amide bioisoterism is a widely used strategy in drug development to fine‐tune physicochemical, pharmacokinetic, and metabolic properties, eliminate toxicity and gain intellectual property rights in uncharted chemical space. Of these, oxetane‐amines offer particularly exciting possibilities as bioisosteres, although they are less frequently investigated than warranted due to the lack of simple and widely applicable synthetic methods. Herein, we report a two‐step, practical, modular, robust, and scalable method for the construction of oxetane‐containing amide bioisosteres that relies on the readily available oxetan‐3‐one. This operationally simple procedure exploits the enhanced reactivity of the keto group of the commercially available oxetan‐3‐one to form amine‐benzotriazole intermediates, which springloaded adducts are then reacted with various aliphatic and aromatic organometallic reagents under mild conditions to afford various amino‐oxetanes in good to high yields. The simplicity and broad applicability of the method greatly facilitates the synthesis of derivatives that were previously difficult or impossible to produce. The usefulness of this method in the field medicinal chemistry was also demonstrated by eliminating the well‐known metabolic problem of ketoconazole. [ABSTRACT FROM AUTHOR]