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Performing transition metal‐catalyzed reactions in cells and living systems has equipped scientists with a toolbox to study biological processes and release drugs on demand. Thus far, an impressive scope of reactions has been performed in these settings, but many are yet to be introduced. Nitrene transfer presents a rather unexplored new‐to‐nature reaction. The reaction products are frequently encountered motifs in pharmaceuticals, presenting opportunities for the controlled, intracellular synthesis of drugs. Hence, we explored the transition metal‐catalyzed sulfimidation reaction in water for future in vivo application. Two Cu(I) complexes containing trispyrazolylborate ligands (Tpx) were selected, and the catalytic system was evaluated with the aid of three fitness factors. The excellent nitrene transfer reactivity and high chemoselectivity of the catalysts, coupled with good biomolecule compatibility, successfully enabled the sulfimidation of thioethers in aqueous media. We envision that this copper‐catalyzed sulfimidation reaction could be an interesting starting point to unlock the potential of nitrene transfer catalysis in vivo. [ABSTRACT FROM AUTHOR]

GDP-mannose transporters (GMTs) have been implicated in the virulence of some important pathogenic fungi, and guanosine diphosphate (GDP) mannose transporters transport GDP-mannose from the cytosol to the Golgi lumen prior to mannosylation, where mannose attaches to the modified protein. GMTs could be potential targets for new antifungal drugs, as disruption of any step in GDP-mannose biosynthesis can affect fungal viability, growth, or virulence. To date, the GDP-mannose transporter has been extensively studied in yeast, but its biological function in fungi, particularly F. graminearum, is still unclear. In this experimental study, the role of the GDP-mannose transporter in F. graminearum was investigated by analysing the VRG4 gene. FgGmtA and FgGmtB were blastp-derived from their Scvrg4 protein sequences and proved to be their functional homologues. The mutant and complementary strains of FgGmtA, FgGmtB and FgGmtA&B genes were generated and used to evaluate the effect of the two GMTs genes on mycelial growth, asexual reproduction, sexual reproduction, cell wall sensitivity, glyphosate synthesis and drug susceptibility. Only in the FgGmtB and FgGmtA&B mutants was the rate of mycelial growth slowed, conidium production increased, sexual reproduction impaired, cell wall sensitivity increased, glycemic content decreased, and drug sensitivity reduced. The results of the pathogenicity assessment of GMTs showed that only FgGmtB affects the patogenicity of F. graminearum. At the same time, the effect of GMTs on the ability of rhinoceros to synthesise DON toxins was investigated and the results showed that the ability of ΔFgGmtB and ΔFgGmtA&B mutants to produce the DON toxin was significantly reduced, and the expression of toxin-related genes was also reduced. [ABSTRACT FROM AUTHOR]

This research work reports the preparation of Ribociclib based on the green chemical principles such as third principle (less hazardous chemical synthesis), fifth principle (Safer solvents) and ninth principle catalysis of green chemistry that were planned and executed. Harmful solvent (chlorinated solvents)-free methodologies were executed. Highly abundant and ecofriendly Fe metal was employed for the reduction of –NO2 group to the corresponding –NH2. Phase transfer catalytic reactions were optimized twice in the coupling reactions by using simple carbonates in the preparation of side chain building and thereafter its coupling with Ribociclib precursor. A potential method for industrial practice has been executed here which is both eco- and economically friendly. [ABSTRACT FROM AUTHOR]

Transition metal-catalyzed asymmetric cyclization of 1,6-enynes is a powerful tool for the construction of chiral nitrogen-containing heterocycles. Despite notable achievements, these transformations have been largely limited to the use of aryl or alkenyl metal reagents, and stereoselective or stereospecific alkylative cyclization of 1,6-enynes remains unexploited. Herein, we report Ni-catalyzed enantioselective reductive anti-arylative cyclization of 1,6-enynes with aryl iodides, providing enantioenriched six-membered carbo- and heterocycles in good yields with excellent enantioselectivities. Additionally, we have realized Ni-catalyzed enantiospecific reductive cis-alkylative cyclization of 1,6-enynes with alkyl bromides, furnishing chiral five-membered heterocycles with high regioselectivity and stereochemical fidelity. Mechanistic studies reveal that the arylative cyclization of 1,6-enynes is initiated by the oxidative addition of Ni(0) to aryl halides and the alkylative cyclization is triggered by the oxidative addition of Ni(0) to allylic acetates. The utility of this strategy is further demonstrated in the enantioselective synthesis of the antiepileptic drug Brivaracetam. Transition metal-catalyzed asymmetric cyclization of 1,6-enynes is a powerful tool for the construction of chiral nitrogen-containing heterocycles, but limiting to the use of aryl or alkenyl metal reagents. Here, the authors report Ni-catalyzed enantioselective anti-arylative cyclization and enantiospecific cis-alkylative cyclization of 1,6-enynes. [ABSTRACT FROM AUTHOR]

This work describes the palladium(II)‐catalyzed regioselective C8‐H olefination of 1‐naphthamides. Interestingly, naphthamide fused lactam 2,3‐dihydro‐1H‐benzo[de]isoquinolin‐1‐one derivatives were also synthesized in the case of a particular class of napthamides. This protocol was found well compatible with a diverse range of acrylates and styrenes leading to product formation in good yields along with a wide functional group tolerance. The developed strategy was further applied to the synthesis of different drug derivatives. [ABSTRACT FROM AUTHOR]

Flow chemistry has recently opened new chemistry windows thanks to the safer use of hazardous and sensitive reagents. Furthermore, flow procedures usually outperform their batch counterparts due to improved mass and heat transfer, offering a good opportunity for industrial application. Herein, a rapid Simmons‐Smith cyclopropanation flow process is presented. Taking advantage of the in situ production of the zinc carbenoid species, several olefins bearing aromatic rings of different electronic nature, aliphatic chains or heterocycles were smoothly cyclopropanated with a residence time of just 15 minutes. In addition, industrial applicability of the protocol is assured thanks to a successful 12‐mmol scale experiment, which represents a 3.59 grams per hour production of a selected example, and to the satisfactory synthesis of pharmaceutical drugs. [ABSTRACT FROM AUTHOR]

α,α-Disubstituted α-amino acids (α-AAs) have improved properties compared to other types of amino acids. They serve as modifiers of peptide conformation and as precursors of bioactive compounds. Therefore, it has been a long-standing goal to construct this highly valuable scaffold efficiently in organic synthesis and drug discovery. However, access to α,α-disubstituted α-AAs is highly challenging and largely unexplored due to their steric constraints. To overcome these, remarkable advances have been made in the last decades. Emerging strategies such as synergistic enantioselective catalysis, visible-light-mediated photocatalysis, metal-free methodologies and CO2 fixation offer new avenues to access the challenging synthesis of α,α-disubstituted α-AAs and continuously bring additional contributions to this field. This review article aims to provide an overview of the recent advancements since 2015 and discuss existing challenges for the synthesis of α,α-disubstituted α-AAs and their derivatives. α,α-Disubstituted α-amino acids (α-AAs) have improved properties compared to other amino acids. Here, the authors provide an overview of the recent advancements since 2015 and discuss existing challenges for their synthesis. [ABSTRACT FROM AUTHOR]

This document provides a summary of the development and application of a palladium-loading ceramic catalytic membrane reactor for the Mizoroki-Heck reaction, a carbon-carbon bond formation strategy in organic synthesis. The researchers successfully demonstrated the use of a palladium-loaded ceramic membrane in the reaction, achieving high yields of desired products. The reactor showed good stability and recyclability, making it a promising approach for efficient and environmentally friendly drug synthesis. The document also includes information on the synthesis of specific compounds and their corresponding spectral data, as well as GCMS analysis of a compound with the molecular formula C14H12O2. [Extracted from the article]

The highly stereoselective synthesis of a series of tetrasubstituted mono‐ as well as disilylated vinylboronates is reported by using the boron‐Wittig approach. The condensation between acylsilanes and gem‐diborylalkanes gave the desired tetrasubstituted olefins in good to excellent yield and high stereoselectivity. Also, a series of trisubstituted silylated vinyl MIDA‐boronates was synthesized by using the boron‐Wittig reaction followed by a transesterification reaction. This methodology allows direct incorporation of B(pin) and TMS groups in the anti‐position of the olefin in a highly stereoselective manner. Further, sequential Suzuki coupling reaction with the silylated vinyl boronic esters generated all‐carbon tetrasubstituted alkenes, which have been applied in the total synthesis of the anticancer drug Tamoxifen and aggregation‐induced luminogen agent TPE‐TF17. [ABSTRACT FROM AUTHOR]

Titanocene conjugates with four different non-steroidal anti-inflammatory drugs (flurbiprofen, naproxen, ibuprofen, and diclofenac; NSAIDs) were obtained for the first time. The spectra of the obtained compounds were recorded, and an unexpectedly strong effect of chiral ligands based on NSAIDs on the chemical shifts of protons of cyclopentadienyl rings of titanocene in 1H NMR spectra was discovered and explained. For all the obtained conjugates, the redox behavior in DMF solution was investigated; the reduction potentials of all titanocene–NSAID compounds were in the range of −0.80 to −0.98 V, which were suitable for their intracellular reduction. The stability of all the conjugates obtained in aqueous media turned out to be many times higher than the stability of titanocene dichloride (the half-life of titanocene–NSAID conjugates was 50–180 minutes, and for one of the conjugates it exceeded 400 minutes). The most cytotoxic of the obtained compounds, the titanocene conjugate with ibuprofen, showed IC50 against the A2780 cell line 35% lower than the original titanocene dichloride and SI = 1.54 in relation to non-tumor human fibroblast cells. [ABSTRACT FROM AUTHOR]

Chemists in the medicinal chemistry field are constantly searching for alternatives towards more sustainable and eco-friendly processes for the design and synthesis of drug candidates. The pharmaceutical industry is one of the most polluting industries, having a high E-factor, which is driving the adoption of more sustainable processes not only for new drug candidates, but also in the production of well-established active pharmaceutical ingredients. Deep eutectic systems (DESs) have emerged as a greener alternative to ionic liquids, and their potential to substitute traditional organic solvents in drug discovery has raised interest among scientists. With the use of DESs as alternative solvents, the processes become more attractive in terms of eco-friendliness and recyclability. Furthermore, they might be more effective through making the process simpler, faster, and with maximum efficiency. This review will be focused on the role and application of deep eutectic systems in drug discovery, using biocatalytic processes and traditional organic chemical reactions, as new environmentally benign alternative solvents. Furthermore, herein we also show that DESs, if used in the pharmaceutical industry, may have a significant effect on lowering production costs and decreasing the impact of this industry on the quality of the environment. [ABSTRACT FROM AUTHOR]

Ultrasonic methods have been very fruitful in studying the physical properties of binary liquid combinations. In this present study, the thermoacoustic behavior of benzyl propionate with dimethyl sulfoxide (DMSO) is observed using ultrasound, density, and viscosity at different temperatures between 308 and 328 K with a phase of 10 °C. Benzyl propionate is a sweet‐smelling liquid that is used in the botanical and fruit fragrance industries, as well as in the flavoring of organic products. DMSO is a dipolar aprotic, naturally soluble compound used for slow drug synthesis, device synthesis, and drug delivery to the body. Estimated values such as adiabatic compressibility, intermolecular free length, internal pressure, and free volume are determined from arbitrary ultrasonic velocity, density, and viscosity data. The same excess parameters of adiabatic compressibility, intermolecular free length, internal pressure, and free volume support finding the nature of the reaction. The sort of interactions has been accounted for utilizing these qualities. In the present work, benzyl propionate with dimethyl sulfoxide has been characterized by using ultrasonic waves and since this wave is a well‐known tool for NDT, so the mixture is properly characterized. These thermoacoustic parameters with different concentrations of DMSO at different temperatures have been used to study the complex formation and binding through intermolecular forces. [ABSTRACT FROM AUTHOR]

A mild and scalable chemo‐enzymatic procedure for the synthesis of the anticancer drug navarixin was developed in aqueous micellar media. We herein, report a greener methodology for the synthesis of a key chiral amine intermediate in the synthesis of navarixin using transaminases. This was obtained in high yields with an enantiomeric excess of >99.9 %. The current synthetic method represents a mild and sustainable procedure to afford the chiral amine intermediate in a single step without the use of expensive chiral ligands and auxiliaries. Furthermore, the chiral amine was used in the synthesis of navarixin which was obtained in high yield and an enantiomeric excess of >97.7 %. [ABSTRACT FROM AUTHOR]

We report a mild, catalytic method for the intermolecular reductive coupling of feedstock dienes and styrenes with ketones. Our conditions allow concomitant formation of a cobalt hydride species and single‐electron reduction of ketones. Subsequent selective hydrogen‐atom transfer from the cobalt hydride generates an allylic radical which can selectively couple with the persistent radical‐anion of the ketone. This radical‐radical coupling negates unfavourable steric interactions of ionic pathways and avoids the unstable alkoxy radical of previous radical olefin‐carbonyl couplings, which were limited, as a result, to aldehydes. Applications of this novel and straightforward approach include the efficient synthesis of drug molecules, key intermediates in drug synthesis and site‐selective late‐stage functionalisation. [ABSTRACT FROM AUTHOR]

Primary aliphatic amines are crucial, and at the very least, millions of tons are required every year. Therefore, significant interest has grown in finding new chemical routes for their synthesis. Additionally, to comply with sustainability requirements, synthetic routes using inexpensive feedstocks are highly prioritized. In this regard, the hydroaminoalkylation (HAA) reaction is highly desirable due to the wide availability and lower price of olefins. Although photoredox catalysis is already known for synthesizing amines, the synthesis of linear aliphatic amines is mostly limited to hydroaminomethylation (HAM) reactions and has never been applied to the synthesis of longer-chain linear aliphatic primary amines. Considering this, the synthesis of functionalized linear aliphatic primary amines is demonstrated by using the decarboxylative radical-polar crossover process, which yielded a wide range of functionalized linear aliphatic amines with excellent yields. The strength of this method is demonstrated by the synthesis of existing drugs and late-stage transformations of complex pharmaceuticals, and elaborated with detailed mechanistic studies. [ABSTRACT FROM AUTHOR]

Cytidine triphosphate (CTP), as a substance involved in the metabolism of phospholipids, proteins and nucleic acids, has precise drug effects and is a direct precursor for the synthesis of drugs such as citicoline. In this study, we established an in vitro six-enzyme cascade system to generate CTP. To avoid thermodynamic bottlenecks, we employed a circuitous and two-stage reaction strategy. Using cytidine as the key substrate, the final product CTP is obtained via the deamination and uridine phosphorylation pathways, relying on the irreversible reaction of cytidine triphosphate synthase to catalyze the amination of uridine triphosphate. Several extremophilic microbial-derived deaminases were screened and characterized, and a suitable cytidine deaminase was selected to match the first-stage reaction conditions. In addition, directed evolution modification of the rate-limiting enzyme CTP synthetase in the pathway yielded a variant that successfully relieved the product feedback inhibition, along with a 1.7-fold increase in activity over the wild type. After optimizing the reaction conditions, we finally carried out the catalytic reaction at an initial cytidine concentration of 20 mM, and the yield of CTP exceeded 82% within 10.0 h. [ABSTRACT FROM AUTHOR]

Aim/Background: The Cytochrome P450 (CYP) enzyme family, consisting of 57 distinct genes, plays a pivotal role in various biological processes. These genes encode enzymes with multifaceted functions, impacting vital processes like arachidonic acid metabolism, xenobiotic detoxification, eicosanoids production, and drug metabolism. Moreover, CYP enzymes are indispensable for the synthesis of bile acids, steroids, and numerous metabolic pathways. They also participate in the hydroxylation of retinoic acid, illustrating their remarkable versatility. While some CYP enzymes still have undiscovered functions, their role continues to captivate researchers across diverse domains. Additionally, mutations in CYP genes can give rise to inborn metabolic disorders, leading to clinically significant diseases, underscoring the importance of CYP enzymes in maintaining metabolic equilibrium and overall well-being. Beyond their initial association with hepatic drug detoxification, recent research has unveiled a broader spectrum of enzymatic processes undertaken by cytochrome P450. The complexity of CYP enzymes is progressively unfolding, emphasizing their clinical significance and opening new avenues for drug development, precision medicine, and patient care. methodology: This abstract presents a comprehensive overview of the literature on cytochrome P450 enzymes and their diverse functions. The information was gathered from a wide range of sources, including scientific articles, textbooks, and research publications. The analysis covers the genetic basis of CYP enzymes, their roles in various metabolic pathways, and the clinical implications of CYP gene mutations. Additionally, the abstract highlights the recent advances in our understanding of CYP enzymes and their expanding role in maintaining human life. Results: The results of this study showcase the remarkable diversity of functions performed by cytochrome P450 enzymes. They are intricately involved in processes critical to human health, ranging from drug metabolism to the synthesis of vital biomolecules. The study underlines the clinical significance of CYP enzymes, as mutations in these genes can lead to severe metabolic disorders and diseases. Furthermore, it emphasizes the evolving understanding of CYP enzyme complexity and its implications for drug development, precision medicine, and patient care. Conclusion: In conclusion, this abstract sheds light on the exceptional versatility and clinical importance of cytochrome P450 enzymes. Their diverse functions have far-reaching consequences for human health, making them a focal point of research in pharmacology and medicine. The evolving understanding of CYP enzyme complexity paves the way for future advancements in drug development and personalized patient care, offering new possibilities for enhancing the well-being of individuals and populations. This research underscores the significance of CYP enzymes and their potential to revolutionize the fields of medicine and pharmacology. [ABSTRACT FROM AUTHOR]

The unique properties of ionic liquids (ILs), such as structural tunability, good solubility, chemical/thermal stability, favorable biocompatibility, and simplicity of preparation, have led to a wide range of applications in the pharmaceutical and biomedical fields. ILs can not only speed up the chemical reaction process, improve the yield, and reduce environmental pollution but also improve many problems in the field of medicine, such as the poor drug solubility, product crystal instability, poor biological activity, and low drug delivery efficiency. This paper presents a systematic and concise analysis of the recent advancements and further applications of ILs in the pharmaceutical field from the aspects of drug synthesis, drug analysis, drug solubilization, and drug crystal engineering. Additionally, it explores the biomedical field, covering aspects such as drug carriers, stabilization of proteins, antimicrobials, and bioactive ionic liquids. [ABSTRACT FROM AUTHOR]

Covering: 2009 up to August 2023 Prenyltransferases (PTs) are involved in the primary and the secondary metabolism of plants, bacteria, and fungi, and they are key enzymes in the biosynthesis of many clinically relevant natural products (NPs). The continued biochemical and structural characterization of the soluble dimethylallyl tryptophan synthase (DMATS) PTs over the past two decades have revealed the significant promise that these enzymes hold as biocatalysts for the chemoenzymatic synthesis of novel drug leads. This is a comprehensive review of DMATSs describing the structure–function relationships that have shaped the mechanistic underpinnings of these enzymes, as well as the application of this knowledge to the engineering of DMATSs. We summarize the key findings and lessons learned from these studies over the past 14 years (2009–2023). In addition, we identify current gaps in our understanding of these fascinating enzymes. [ABSTRACT FROM AUTHOR]

The effective synthesis of N-benzyl cyclo-tertiary amines using imine reductase, key components in natural products and pharmaceutical synthesis, is a green approach. Traditional methods faced challenges with enzyme activity and selectivity. This study focused on enhancing Mesorhizobium imine reductase (MesIRED) for better N-benzyl cyclo-tertiary amine production. Through alanine scanning and consensus mutation, 12 single-site MesIRED mutants were identified from 23 candidates, showing improved conversion of N-benzylpyrrolidine and N-benzylpiperidine. Notably, mutants from I177, V212, I213, and A241 significantly boosted conversions. The best-performing mutant for N-benzylpyrrolidine, MesIREDV212A/I213V (M1), increased conversion from 23.7% to 74.3%. For N-benzylpiperidine, MesIREDV212A/I177A/A241I (M2) enhanced conversion from 22.8% to 66.8%. Tunnel analysis revealed M1 and M2 have more efficient tunnels for larger product movement compared to wild-type MesIRED. Using recombinant E. coli coexpressing MesIRED and glucose dehydrogenase (GDH), high conversions were achieved: 75.1% for N-benzylpyrrolidine (M1) and 88.8% for N-benzylpiperidine (M2). A preparative experiment resulted in 86.2% conversion and 60.2% yield for N-benzylpiperidine. This research offers an efficient method for engineering IRED, significantly improving conversion and selectivity for N-benzyl cyclo-tertiary amines, aiding drug synthesis and providing insights into rational design of other enzymes. [ABSTRACT FROM AUTHOR]

A cobalt(II) perchlorate hexahydrate coordinated synthesis of dihydropyrimidin‐ones and ‐thiones through sonochemistry is developed. Herein, the reaction was demonstrated as a simple, efficient, and one‐pot method for synthesizing a series of interesting 3,4‐dihydropyrimidin‐2(1H)‐ones. Further, the reaction mechanism was investigated using mass spectrometry and density functional theory calculations suggesting that a Lewis acid character of cobalt(II) perchlorate hexahydrate plays a crucial role in coordinating carbonyl functionalities and stabilizing the polar intermediates like imine–enamine which further led to cyclized dihydropyrimidin‐ones and ‐thiones. This methodology was further explored to synthesize a gram‐scale synthesis of monastrol drug, a kinase inhibitor. [ABSTRACT FROM AUTHOR]

The development of advanced methods for the synthesis of nano- and microparticles in the field of biomedicine is of high interest due to a range of reasons. The current synthesis methods may have limitations in terms of efficiency, scalability, and uniformity of the particles. Here, we investigate the synthesis of submicron calcium carbonate using a microfluidic chip with a T-shaped oil supply for droplet-based synthesis to facilitate control over the formation of submicron calcium carbonate particles. The design of the chip allowed for the precise manipulation of reaction parameters, resulting in improved porosity while maintaining an efficient synthesis rate. The pore size distribution within calcium carbonate particles was estimated via small-angle X-ray scattering. This study showed that the high porosity and reduced size of the particles facilitated the higher loading of a model peptide: 16 vs. 9 mass.% for the particles synthesized in a microfluidic device and in bulk, correspondingly. The biosafety of the developed particles in the concentration range of 0.08–0.8 mg per plate was established by the results of the cytotoxicity study using mouse fibroblasts. This innovative approach of microfluidically assisted synthesis provides a promising avenue for future research in the field of particle synthesis and drug delivery systems. [ABSTRACT FROM AUTHOR]

Some antibiotics that are frequently employed are β-lactams. In light of the hydrolytic process of β-lactamase, found in Gram-negative bacteria, inhibitors of β-lactamase (BLIs) have been produced. Examples of first-generation β-lactamase inhibitors include sulbactam, clavulanic acid, and tazobactam. Many kinds of bacteria immune to inhibitors have appeared, and none cover all the β-lactamase classes. Various methods have been utilized to develop second-generation β-lactamase inhibitors possessing new structures and facilitate the formation of diazabicyclooctane (DBO), cyclic boronate, metallo-, and dual-nature β-lactamase inhibitors. This review describes numerous promising second-generation β-lactamase inhibitors, including vaborbactam, avibactam, and cyclic boronate serine-β-lactamase inhibitors. Furthermore, it covers developments and methods for synthesizing MβL (metallo-β-lactamase inhibitors), which are clinically effective, as well as the various dual-nature-based inhibitors of β-lactamases that have been developed. Several combinations are still only used in preclinical or clinical research, although only a few are currently used in clinics. This review comprises materials on the research progress of BLIs over the last five years. It highlights the ongoing need to produce new and unique BLIs to counter the appearance of multidrug-resistant bacteria. At present, second-generation BLIs represent an efficient and successful strategy.

Fluorine holds a prominent position within the realm of drug discovery and development, substantiated by its presence in approximately 25% of drugs approved by the US Food and Drug Administration (FDA). Consequently, the advancement of new fluorination reactions stands as a pivotal area in medicinal chemistry. In particular, the monofluoro-, difluoromethyl-, and trifluoromethyl- are three groups that appear most frequently in drug structure. Quinoline, owing to its privileged structural status, plays a crucial role in drug design and synthesis. Various approaches have been documented for the direct difluoromethylation of the C-2 and C-4 positions of the quinoline ring. However, achieving direct C-3 difluoromethylation has remained an elusive objective. In this study, we introduce a novel method for effecting the direct difluoromethylation at the C-3 position of the quinoline ring. Comprehensive characterizations, including 1H-NMR, 13C-NMR, and 19F-NMR for all compounds are performed. We believe that this novel method will open a new way to access the hitherto untapped C-3-difluoromethylation active compounds.

This article discusses the synthesis of functionalized spirooxindole polycycles, which are found in many bioactive natural products. The authors describe strategies for the concise synthesis of these complex molecules, including enantiomerically enriched derivatives. They utilize cyclic 1,3-dione derivatives as reactants or as condition-tuning molecules to form the polycyclic systems. The article also explores the formation of spirooxindole pyran polycycles through dynamic stereoselective aldol-oxacyclization cascade reactions. Additionally, the authors discuss the asymmetric construction of spirooxindole polycycles bearing furan-fused rings through Michael-Henry reactions. The use of cyclic 1,3-dione derivatives is shown to alter the reaction conditions and products. The authors conclude by highlighting the potential applications of their synthesis strategies in drug discovery and biomedical research. [Extracted from the article]

The protection of carbonyl functional groups via dithioacetalization with thiols or dithiols plays a significant role in multi-step organic syntheses, such as natural products and drug synthesis. Therefore, dithioacetalization has always been cherished as one of the most important organic transformations in both academic and industrial research. Numerous synthetic strategies for the dithioacetalization of carbonyl compounds have been reported in the literature for the synthesis of industrially valuable organosulfur compounds or precursors like acyclic dithioacetals, dithiolanes, and dithianes. Regardless of having many conventional efficient synthetic protocols, greener approaches have been recognized as a viable alternative due to environmental and health concerns. Consequently, the growing trend of developing greener methods stimulated by the green chemistry concept for dithioacetalization is inevitable. The present review is aimed to highlight the recent advances in the greener and convenient synthetic approaches employed for the dithioacetalization of carbonyl compounds. [ABSTRACT FROM AUTHOR]

Bioorthogonal chemistry is a promising toolbox for dissecting biological processes in the native environment. Recently, bioorthogonal reactions have attracted considerable attention in the medical field for treating diseases, since this approach may lead to improved drug efficacy and reduced side effects via in situ drug synthesis. For precise biomedical applications, it is a prerequisite that the reactions should occur in the right locations and on the appropriate therapeutic targets. In this minireview, we highlight the design and development of targeted bioorthogonal reactions for precise medical treatment. First, we compile recent strategies for achieving target‐specific bioorthogonal reactions. Further, we emphasize their application for the precise treatment of different therapeutic targets. Finally, a perspective is provided on the challenges and future directions of this emerging field for safe, efficient, and translatable disease treatment. [ABSTRACT FROM AUTHOR]

Thia-Michael addition reactions are significant for organic syntheses of important class of compounds to form C-S bond and its derivatives. It shows the prominent feature in medicinal field and material science. This review is focused on various methods towards thia-Michael adducts using Michael addition of sulfur containing electron rich species (Michael donor) on electron poor olefins (Michael acceptor). The C-S bond is ideal of making bioactive molecules generalized for the synthesis of various drug molecules and applied in field as insect sprays and polymer substances which are common for daily life. Due to the importance of C-S bond in recent years, novel methods for C-S bond formation were developed, which are more convenient with environment. [ABSTRACT FROM AUTHOR]

The Mannich reaction is commonly used to introduce N atoms into compound molecules and is thus widely applied in drug synthesis. The Mannich reaction accounts for a certain proportion of structural modifications of natural products. The introduction of Mannich bases can significantly improve the activity, hydrophilicity, and medicinal properties of compounds; therefore, the Mannich reaction is widely used for the structural modification of natural products. In this paper, the application of the Mannich reaction to the structural modification of natural products is reviewed, providing a method for the structural modification of natural products. [ABSTRACT FROM AUTHOR]

In the current study, dapsone and different 4-acyl pyrazolone derivatives have been used to synthesise various Cu(II) and Ni(II) based heterochelates. Elemental analysis, ¹H NMR, IR, and mass spectroscopy have been utilized to check the structure of the tetra dentate DPL1 to DPL5 ligands, and FAB mass spectroscopy as well as temperature investigations (TGA/DTG and DSC) have been utilized to approve the structure of the Cu(II) and Ni(II) heterochelates. All the synthesized compounds have been examined for their in vitro biological study against two Gram +ve (Bacillus cereus, Bacillus megaterium) and two Gram -ve (Escherichia coli, Enterobacter aerogene) microorganisms as well as their MIC against two Gram +ve (Bacillus subtilis, Staphylococcus aureus) and two Gram -ve (Escherichia coli, Serratia marcescens) microorganisms. The outcomes demonstrate the tremendous promise and importance of novel bis-pyrazolone heterochelates based on dapsone for further study. [ABSTRACT FROM AUTHOR]

Imidazo[1,2-a]pyrimidine derivatives are a class of biologically active parent nucleus structures containing both imidazole and pyrimidine rings, which are important intermediates for the synthesis of a variety of drugs. This class of structures has attracted a lot of attention of researchers, and more and more synthetic strategies have been developed and reported. Currently, the main synthetic strategies are one-pot multi-component methods, microwave radiation, ultrasonic irradiation and other auxiliary Knoevenagel condensation and Michael addition methods to obtain these compounds, with the aim of achieving high yields, low time consumption and environmental friendliness. This review comprehensively summarizes the various synthetic methods as well as mechanism recently reported for the construction of this remarkable backbone structure and further used for the development of new chemical synthesis strategies and drug development as it has a wide range of applications in medicinal chemistry. In order to provide some impetus to the research of synthetic methods for this structure. [ABSTRACT FROM AUTHOR]

Flavin-dependent monooxygenases (FMOs) have raised substantial interest as catalysts in monooxygenation reactions, impacting diverse fields such as drug metabolism, environmental studies, and natural product synthesis. Their application in biocatalysis boasts several advantages over conventional chemical catalysis, such as heightened selectivity, safety, sustainability, and eco-friendliness. In the realm of biomedicine, FMOs are pivotal in antibiotic research, significantly influencing the behavior of natural products, antimicrobial agents, and the pathways critical to drug synthesis They are also underscored as potential pharmaceutical targets, pivotal in opposing disease progression and viable for therapeutic intervention. Additionally, FMOs play a substantial role in environmental science, especially in pesticide processing and in preserving plant vitality. Their involvement in the biosynthesis of compounds like polyethers, tropolones, and ω-hydroxy fatty acids, with remarkable regio- and stereoselectivity, renders them indispensable in drug discovery and development. As our comprehension of FMOs' catalytic mechanisms and structures advances, through the use of cutting-edge biotechnologies like computational design and directed evolution, FMOs are poised to occupy an increasingly significant role in both scientific exploration and industrial applications. [ABSTRACT FROM AUTHOR]

The major drawback of current treatment of infectious diseases are challenging due to resistance to antimicrobial agents and their side effects. In order to overcome this situation, it is necessary to continue the search for new antibacterial agents. In recent scenario heterocycles plays a major role in drug synthesis. In that respect oxadiazole plays a significant role among other heterocycles. From the literature survey oxadiazole was found to be having diverse activity like anti-inflammatory, antimicrobial, antifungal, antiviral, analgesic, anti-mycobacterial, antidepressent and anticancer etc. So it was planned to synthesize a novel series of 1,3,4 oxadiazole derivatives from reaction between 4 morpholin 4-yl benzonitrile treated with hydrogen sulphide gives 4-(morpholin–4yl)benzenecarbothioamide which was cyclisation and hydrozide gives 4- methyl-2-[4-(morpholine-4-yl)-phenyl]-1,3-thiazole-5-carbohydrazide it was under goes cyclisation to yield resultant compound 1,3,4-oxadiazole derivatives (SMV-IVA-IVF). All the compounds synthesized were confirmed by spectral data and evaluated for their antibacterial and antifungal (Cup-Plate method) activity. The compounds SMV-IVD and BM-IVE have shown good antibacterial and antifungal activity and remaining shows poor activity. [ABSTRACT FROM AUTHOR]

Testosterone (TS) is an important androgen drug and a precursor of steroid drug synthesis. Ketoreductase 2 (KR-2) (GenBank accession no. ABP64403.1) is observed to stereo-selectively catalyze the bioreduction of 4-androstene-3,17-dione (4-AD) to testosterone and contribute to the regeneration of NADH using isopropanol as a co-substrate. The Km value of KR-2 was 2.22 mmol/L with 4-AD, and the optimal pH was 6.5–7.0. The enzyme is stable and demonstrates relatively high-level enzyme activity at 40 °C. Acetone significantly inhibits this activity. This inhibition was overcome using an intermittent vacuum during the reaction process. Finally, the amount of TS reached 65.42 g/L after a 52 h reaction with 65.8 g/L 4-AD, 10% isopropanol, and 2 g/L β–NAD+ at 40 °C, with a conversion rate of 98.73%. A total of 6.15 g of TS was obtained from 6.58 g of 4-AD after the reaction and purification; the HPLC purity was 99.82%, and the overall yield was 92.81%. This enzyme provides a promising route for the green biosynthesis of testosterone for industrial applications. [ABSTRACT FROM AUTHOR]

Nanomedicine and nanodelivery are a very fast-growing domains of science where materials in the nanoscale range are synthesized for the conjugation of drug molecules to deliver therapeutic agents in a controlled way for effective therapy. Nanomedicine has several outstanding applications in the treatment of various diseases, such as chemotherapeutic agents, biological agents, and immunotherapy agents. Recent advances in materials science and protein engineering have created targeted delivery of therapeutic enzymes using nanocarriers (NCs) for the effective treatment of cancer, AIDS (acquired immune deficiency syndrome), etc. Several NCs have been approved as drug delivery agents for clinical use as a current treatment model. Drugs associated with specially designed carriers such as cell-specific enzymes can lead to effective targeting. In this way, a drug can be transferred to the position of action, thus minimizing its influence on other essential tissues and undesirable side effects. This type of therapy is crucial for cases with a lack of surety about drug concentration, dose, and respective therapeutic outcomes. Despite their advantages, it has some disadvantages, such as toxicity, environmental harm, and organ damage caused by nanoparticles. But overall, nanoparticle-mediated therapeutic enzyme delivery could lead to the establishment of promising strategies for the prevention, diagnosis, management, and cure of many diseases. Therapeutic enzymes hold a promising place in the medical industry as it is used in disease treatment, diagnosis, and in drug synthesis. However, their stability, pharmacodynamic and pharmacokinetic behavior, and reusability is a major concern. These challenges can be addressed with suitable drug carriers. This review deals with some therapeutic enzymes (a glance) and their industrial application and gives details of nanoparticles used in drug delivery, especially the delivery of therapeutic enzymes using nanoparticle and their prospects. [ABSTRACT FROM AUTHOR]

Stroke is accounted as the second-most mortality and adult disability factor in worldwide, while causes the bleeding promptly and lifetime consequences. The employed functional recovery after stroke is highly variable, allowing to deliver proper interventions to the right stroke patient at a specific time. Accordingly, the multidisciplinary nursing team, and the administrated drugs are major keybuilding- blocks to enhance stroke treatment efficiency. Regarding the healthcare team, adequate continuum of care have been declared as an integral part of the treatment process from the pre-hospital, in-hospital, to acute post-discharge phases. As a curative perspective, drugs administration is also vital in surviving at the early step and reducing the probability of disabilities in later. In this regard, nanotechnology-based medicinal strategy is exorbitantly burgeoning. In this review, we have highlighted the effectiveness of current clinical care considered by nursing teams to treat stroke. Also, the advancement of drugs through synthesis of miniaturized nanodrug formations relating stroke treatment is remarked. Finally, the remained challenges toward standardizing the healthcare team and minimizing the nanodrugs downsides are discussed. The findings ensure that future works on normalizing the healthcare nursing teams integrated with artificial intelligence technology, as well as advancing the operative nanodrugs can provide value-based stroke cares. [ABSTRACT FROM AUTHOR]

Copper (Cu) is an essential element that is involved in a variety of biochemical processes. Both deficiency and accumulation of Cu are associated with various diseases; and a high amount of accumulated Cu in cells can be fatal. The production of reactive oxygen species (ROS), oxidative stress, and cuproptosis are among the proposed mechanisms of copper toxicity at high concentrations. Elesclomol (ELC) is a mitochondrion-targeting agent discovered for the treatment of solid tumors. In this review, we summarize the synthesis of this drug, its mechanisms of action, and the current status of its applications in the treatment of various diseases such as cancer, tuberculosis, SARS-CoV-2 infection, and other copper-associated disorders. We also provide some detailed information about future directions to improve its clinical performance. [ABSTRACT FROM AUTHOR]

Organosilicon compounds have shown tremendous potential in drug discovery and their synthesis stimulates wide interest. Multicomponent cross-coupling of alkenes with silicon reagents is used to yield complex silicon-containing compounds from readily accessible feedstock chemicals but the reaction with simple alkenes remains challenging. Here, we report a regioselective silylalkylation of simple alkenes, which is enabled by using a stable Ni(II) salt and an inexpensive trans−1,2-diaminocyclohexane ligand as a catalyst. Remarkably, this reaction can tolerate a broad range of olefins bearing various functional groups, including alcohol, ester, amides and ethers, thus it allows for the efficient and selective assembly of a diverse range of bifunctional organosilicon building blocks from terminal alkenes, alkyl halides and the Suginome reagent. Moreover, an expedient synthetic route toward alpha-Lipoic acid has been developed by this methodology. Multicomponent cross-coupling of alkenes with silicon reagents is used to yield complex silicon-containing compounds from readily accessible feedstock chemicals but the reaction with simple alkenes remains challenging. Here, the authors report a regioselective silylalkylation of simple alkenes, which is enabled by using a stable Ni(II) salt and an inexpensive trans-1,2-diaminocyclohexane ligand as a catalyst. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: L‐Hexoses are key components of many biologically relevant natural products and pharmaceuticals. As rare sugars, L‐hexoses are not readily obtained from natural sources. Access to L‐hexose building blocks from commercially available and inexpensive D‐sugars is highly desirable from the viewpoints of organic synthesis and drug discovery. As demonstrated by the convenient preparation of L‐glucosyl, L‐galactosyl, and L‐mannosyl fluorides from readily available β‐D‐C‐glucosyl, β‐D‐C‐mannosyl, and β‐D‐C‐galactosyl derivatives, we describe a novel and efficient approach to the demanding L‐glycosyl fluorides. The transformation features the installation of anomeric hydroxymethyl group under mild conditions and C1‐to‐C5 switch of sugar rings through radical decarboxylative fluorination of uronic acids. The power of this protocol is highlighted by the first assembly of a pentasaccharide repeating unit of Pseudomonas ATCC 31554 extracellular polysaccharide (S‐88). This synthesis relies on the efficient extension of sugar chain at the sterically hindered hydroxy group and the facile introduction of L‐mannosyl unit using L‐mannosyl fluoride as glycosylating agent. The methods developed in this work would provide new tools to the arsenal of synthesis of L‐sugar building blocks and of assembly of glycans containing L‐sugar moieties. [ABSTRACT FROM AUTHOR]

Synthetic polypeptides are biocompatible and biodegradable macromolecules whose composition and architecture can vary over a wide range. Their unique ability to form secondary structures, as well as different pathways of modification and biofunctionalization due to the diversity of amino acids, provide variation in the physicochemical and biological properties of polypeptide-containing materials. In this review article, we summarize the advances in the synthesis of polypeptides and their copolymers and the application of these systems for drug delivery in the form of (nano)particles or hydrogels. The issues, such as the diversity of polypeptide-containing (nano)particle types, the methods for their preparation and drug loading, as well as the influence of physicochemical characteristics on stability, degradability, cellular uptake, cytotoxicity, hemolysis, and immunogenicity of polypeptide-containing nanoparticles and their drug formulations, are comprehensively discussed. Finally, recent advances in the development of certain drug nanoformulations for peptides, proteins, gene delivery, cancer therapy, and antimicrobial and anti-inflammatory systems are summarized. [ABSTRACT FROM AUTHOR]

Polyphenyls and their derivatives, which are used in heat exchangers, drug synthesis, organic synthesis, and so on, have attracted the attention of researchers in various fields for many years. In this paper, we determine the expected values of the augmented Zagreb and arithmetic-geometric indices for this class of conjugated hydrocarbons. The comparisons between the expected values of these indices concerning the random polyphenyl chains have been determined explicitly. The graphical illustrations have been given in terms of the differences between the expected values of these indices. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify phenolic compounds in walnut leaves from northern Iraq and evaluate their ability to act as antibacterial and antioxidant agents. Phenolic compounds were determined by reversed‐phase HPLC. Antibacterial activity was tested against various bacteria. Antioxidant properties were evaluated by various assays, including reducing power and DPPH radical scavenging activity. The HPLC profiles of walnut leaf fractions revealed quercetin, hydroquinone, 4‐hydroxybenzoic acid, and caffeic acid in three fractions. The inhibitory activity of DPPH was determined as 47.66, 32.41, and 51.90 μg/mL for fractions I, II, and III, respectively. For ferric reducing power activity, fraction II > fraction III > fraction I and the FRAP activity was observed as 64.43, 73.19, and 68.18 μg/mL for fractions I, II, and III, respectively. All extracted fractions had antibacterial properties against all bacterial strains tested. Observations showed that fraction I was able to produce similar zones of inhibition as streptomycin in most cases. These results suggest that the fractions of this plant extract are plausible natural antioxidants that could be used as prime candidates for the synthesis of antioxidant drugs that can be used for the treatment of many oxidative stress‐related diseases. [ABSTRACT FROM AUTHOR]

An efficient and scalable Pd‐catalyzed decarboxylative cross‐coupling strategy for the synthesis of carbazoles has been developed by using N‐aryl anthranilic acids. By employing a well‐designed catalytic system, this protocol access diverse carbazole derivatives via a C−C bond‐formation in one‐pot. The substituted carbazoles were obtained in good to excellent yields with high functional‐group tolerance. We have also demonstrated the gram‐scale synthesis of the anti‐cancer drug Ellipticine by utilizing this methodology. This concise and scalable total synthesis of ellipticine exemplifies the efficiency of our methodology in producing this significant anti‐cancer compound. [ABSTRACT FROM AUTHOR]

Geminal cross couplings using multiple components enable the formation of several different bonds at one site in the building of tertiary and quaternary alkanes. Nevertheless, there are remaining issues of concern—cleavage of two geminal bonds and control of selectivity present challenges. We report here the geminal cross couplings of three components by reactions of dihaloalkanes with organomagnesium and chlorosilanes or alkyl tosylates by Cr catalysis, affording the formation of geminal C−C/C−Si or C−C/C−C bonds in the creation of tertiary and quaternary alkanes. The geminal couplings are catalyzed by low‐cost CrCl2, enabling the sluggishness of competitive Kumada‐type side couplings and homocouplings of Grignard reagents, in achieving high chemoselectivity. Experimental and theoretical studies indicate that two geminal C‐halide bonds are continuously cleaved by Cr to afford a metal carbene intermediate, which couples with a Grignard reagent, followed by silylation, in the formation of geminal C−C and C−Si bonds via a novel inner‐sphere radical coupling mechanism. These three‐component geminal cross couplings are value‐addition to the synthesis of commercial drugs and bioactive molecules in medicinal chemistry. [ABSTRACT FROM AUTHOR]

Herein, a direct and efficient electrochemical method for the synthesis of monofluoroalkene products was promoted using gem-difluoroalkenes and unactivated alkyl halides as starting materials with a nickel catalyst. A plausible mechanism involving an alkyl radical intermediate was proposed based on detailed mechanistic studies. Accompanied by the advantages of electrochemistry, the broad substrate scope of primary, secondary, and tertiary alkyl halides, and excellent functional group tolerance, as well as good Z-selectivity and late-stage modification of bio-relevant molecules made the established method greener and more economic, which could make it further applicable in organic synthesis and drug discovery. [ABSTRACT FROM AUTHOR]

Automating retrosynthesis with artificial intelligence expedites organic chemistry research in digital laboratories. However, most existing deep-learning approaches are hard to explain, like a "black box" with few insights. Here, we propose RetroExplainer, formulizing the retrosynthesis task into a molecular assembly process, containing several retrosynthetic actions guided by deep learning. To guarantee a robust performance of our model, we propose three units: a multi-sense and multi-scale Graph Transformer, structure-aware contrastive learning, and dynamic adaptive multi-task learning. The results on 12 large-scale benchmark datasets demonstrate the effectiveness of RetroExplainer, which outperforms the state-of-the-art single-step retrosynthesis approaches. In addition, the molecular assembly process renders our model with good interpretability, allowing for transparent decision-making and quantitative attribution. When extended to multi-step retrosynthesis planning, RetroExplainer has identified 101 pathways, in which 86.9% of the single reactions correspond to those already reported in the literature. As a result, RetroExplainer is expected to offer valuable insights for reliable, high-throughput, and high-quality organic synthesis in drug development. Automating retrosynthesis prediction in organic chemistry is a major application of ML. Here the authors present RetroExplainer, which offers a high-performance, transparent and interpretable deep-learning framework providing valuable insights for drug development. [ABSTRACT FROM AUTHOR]

Synthesis of anticancer drug bicalutamide promoted by visible light in one step from the corresponding N‐arylacrylamide is described. This approach involves a one‐pot hydroxysulfonylation reaction through a photocatalytic redox process. The use of Na2Eosin Y as photocatalyst and blue light allows the access to a broad range of α‐hydroxysulfonylamides bearing a quaternary center in moderate to good yields with complete regioselectivity via radical process. [ABSTRACT FROM AUTHOR]

Molecular editing, including peripheral and skeletal editing, is an area of interest in the field of organic synthesis. Typically, the peripheral editing of C―H bonds is conventionally used for molecular editing. By contrast, skeletal editing is a novel method, which has broader applications in total synthesis and drug development, with advantages of easy operation, high specificity, and simple synthetical routes. This review introduces two skeletal editing examples using common reactions. By comparisons with conventional methods, the applications of molecular editing in drug synthesis are revealed. Moreover, this review predicts the future applications of molecular editing by presenting some state-of-the-art developments in this field. [ABSTRACT FROM AUTHOR]

Nanoparticles are typically nanoscopic materials with at least one of the dimensions below 100 nm having diverse applications in many industries. The latest developments in nanotechnology provide a wide range of methods for studying and monitoring various medical and biological processes at the nanoscale. Nanoparticles can help diagnose and treat diseases, such as cancer, by carrying drugs directly to cancer cells. They can also be used to detect disease biomarkers in the body, helping to provide early diagnosis. It is plausible that nanoparticles could be used in theranostic applications and targeted drug delivery. This could significantly improve patient outcomes and reduce the amount of time, effort, and money needed to diagnose and treat diseases. It could also reduce the side effects of treatments, providing more precise and effective treatments. Nanoparticles for biomedical applications include polymeric and metal nanoparticles; liposomes and micelles; dendrimers and quantum dots; etc. Among the nanoparticles, gold nanoparticles (GNPs) have emerged as a promising platform for drug delivery applications. GNPs are highly advantageous for drug delivery applications due to their excellent biocompatibility, stability, and tunable physical and chemical properties. The present review provides an in-depth discussion of the various approaches to GNPs synthesis and drug delivery applications. [ABSTRACT FROM AUTHOR]