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Steroidal–nitroxide hybrid molecules and non-radical controls were synthesised in good yields using simple carbodiimide coupling. An unexpected product arose from reactions between the nitroxide moiety and the solvent THF. Methoxyamine derivatives of the nitroxide drug hybrids were produced using Fenton chemistry without side reactions occurring on the steroid. The hybrid compounds bind to the glucocorticoid receptor and are relevant for the study of radical biological chemistry and redox-related disease processes. [ABSTRACT FROM AUTHOR]

The use of (para)-formaldehyde for the methylation/alkylation of C(sp2)–H and N–H bonds, utilizing a combination of silane and hexafluoroisopropanol (HFIP) as activators, is reported. Overcoming the complexity of C(sp2)–H methylation on aryl and indole substrates, the process utilizes a Friedel–Crafts alkylation, followed by silane as a hydride donor, under a mild acidic medium. The method has been employed for the synthesis of the antifungal drug butenafine and a derivative of the non-steroidal anti-inflammatory drug (NSAID) flurbiprofen. [ABSTRACT FROM AUTHOR]

Nitrogen-containing heterocycles have been desirable targets for synthesis for many years because of their structural diversity and biological significance. Five-membered heterocyclic rings, or pyrazole, are a flexible starting point for the design of effective bioactive compounds and are widely used in medicinal chemistry, drug discovery, agrochemistry, coordination chemistry, and organometallic chemistry. Pyrazole derivatives have played an important role in heterocyclic chemistry and have been extensively studied owing to their ease of access, diversified chemical reactivity, and broad biological properties, including antibacterial, anti-inflammatory, anticancer, analgesic, anticonvulsant, anthelmintic, antioxidant, and herbicidal properties. Pyrazole nuclei are synthesized via a variety of methods, including the multicomponent approach, dipolar cycloaddition, cyclocondensation of hydrazine with a carbonyl system, heterocyclic system, and multicomponent approach. The current review is an attempt to understand the chemistry and medicinal importance of the pyrazole-containing marketed drugs reported to date, which will undoubtedly assist the scientific community in making further advances in the isolation and synthesis of pyrazole-based novel bioactive compounds. [ABSTRACT FROM AUTHOR]

The p-methoxycinnamoyl group contained in the compounds extracted from Scrophularia buergeriana, which is a traditional medicinal herb in China, exhibits a remarkable neuroprotective effect. Based on the p-methoxycinnamoyl group, these two cinnamide derivatives, namely, (E)-3-(4-bromophenyl)-1-(4-(4-chlorobenzyl)piperazin-1-yl)prop-2-en-1-one (6a) and (E)-1-(4-(4-chlorobenzyl)piperazin-1-yl)-3-(4-chlorophenyl)prop-2-en-1-one (6b), were designed and synthesized. The target compounds were represented by High-resolution mass spectra, 1H NMR spectra, 13C NMR spectra, and single-crystal X-ray diffraction. According to the results of single-crystal X-ray diffraction, indicating that compound 6a crystallizes in the monoclinic system and compound 6b crystallizes in the triclinic system, and they both have a stacked-layer 3-D structure. Hirshfeld surface indicated that compounds 6a and 6b exist H...H, O...H, C...H, and π...π intermolecular interactions. Furthermore, their neuroprotective effects were further evaluated against glutamate-induced PC12 cell injury. These results indicate that the target compounds exhibit potent activities against glutamine-induced neurotoxicity in PC12 cells. In vivo experiments demonstrated that compounds 6a and 6b have good protective effects in high doses on bilateral common carotid artery ligation. A simple synthesis and structure of two cinnamide derivatives, and biological activity was evaluated by MTT assay. [ABSTRACT FROM AUTHOR]

Thiazole derivatives have long been a hot topic in pharmaceutical research and remain among the greatest active fields in heterocyclic chemistry. Thiazole derivatives, as one of the potentially favored structure, have been extensively desirable by industrial and medicinal researchers and have gained significant success in the previous decades due to their various biological activities, such as anticancer, antibacterial, antifungal, anti-HIV, antiulcer, and anti-inflammatory activity. In addition, many thiazole drugs are well-known pharmaceuticals on the market. This review summarizes the freshly synthesized routes and prospective biological activities of thiazole derivatives. In addition, it highlights thiazoles as treatment drugs in clinical trials or approved by the FDA and spotlights on some of their industrial applications. On the other hand, one of the goals of this review is to open up prospects for the future design, development, and usage of thiazole derivatives as potent drugs. [ABSTRACT FROM AUTHOR]

Biomaterials have been the subject of extensive research, and their applications in medicine and pharmacy are expanding rapidly. Collagen and its derivatives stand out as valuable biomaterials due to their high biocompatibility, biodegradability, and lack of toxicity and immunogenicity. This review comprehensively examines collagen from various sources, its extraction and processing methods, and its structural and functional properties. Preserving the native state of collagen is crucial for maintaining its beneficial characteristics. The challenges associated with chemically modifying collagen to tailor its properties for specific clinical needs are also addressed. The review discusses various collagen-based biomaterials, including solutions, hydrogels, powders, sponges, scaffolds, and thin films. These materials have broad applications in regenerative medicine, tissue engineering, drug delivery, and wound healing. Additionally, the review highlights current research trends related to collagen and its derivatives. These trends may significantly influence future developments, such as using collagen-based bioinks for 3D bioprinting or exploring new collagen nanoparticle preparation methods and drug delivery systems. [ABSTRACT FROM AUTHOR]

AbstractThiazole is a sulfur and nitrogen-containing five-membered heteroaromatic ring in many FDA-approved drugs and numerous experimental leads. To facilitate access to this structure, several novel methodologies have been developed using easily accessible starting materials and more environmentally friendly protocols. This review focuses on all recently developed methods (2013–2024) that utilized homogeneous or heterogeneous catalyzed methods to synthesize 1,3-thiazole and provides thorough information on the diverse therapeutic applicability of thiazole derivatives in drug discovery and development. Furthermore, this review will ameliorate the understanding of synthetic and medicinal chemists in selecting green and ecological methodologies to synthesize thiazoles judicially. [ABSTRACT FROM AUTHOR]

Cancer is measured as a major threat to human life and is a leading cause of death. Millions of cancer patients die every year, although a burgeoning number of researchers have been making tremendous efforts to develop cancer medicine to fight against cancer. Owing to the complexity and heterogeneity of cancer, lack of ability to treat deep tumor tissues, and high toxicity to the normal cells, it complicates the therapy of cancer. However, bacterial derivative-mediated drug delivery has raised the interest of researchers in overcoming the restrictions of conventional cancer chemotherapy. In this review, we show various examples of tumor-targeting bacteria and bacterial derivatives for the delivery of anticancer drugs. This review also describes the advantages and limitations of delivering anticancer treatment drugs under regulated conditions employing these tumor-targeting bacteria and their membrane vesicles. This study highlights the substantial potential for clinical translation of bacterial-based drug carriers, improve their ability to work with other treatment modalities, and provide a more powerful, dependable, and distinctive tumor therapy. [ABSTRACT FROM AUTHOR]

Herein, we report an organic photoredox-catalyzed hydroazidation of trifluoromethyl alkenes with user-friendly trimethylsilyl azide (TMSN3), enabling a direct access to a broad range of valuable β-CF3-azides with exclusive selectivity under mild reaction conditions. The synthetic utility of this reaction was demonstrated by the late-stage modification of complex drug derivatives, scale-up of the reaction and diverse further derivatizations of the β-CF3-azide product. [ABSTRACT FROM AUTHOR]

New (bi)pyridine derivatives of the antimicrobial drug ornidazole were synthesized by alkylation of pyridyl- and 2,2′-bipyridyl-phenolic derivatives for the first time. The proposed methodology makes it possible to expand the range of ornidazole derivatives with increased antibacterial activity. [ABSTRACT FROM AUTHOR]

Context: For the first time, the use of monocyclic rings C18 and B9N9 as sensors for the sensing of carbazole-based anti-cancer drugs, such as tetrahydrocarbazole (THC), mukonal (MKN), murrayanine (MRY), and ellipticine (EPT), is described using DFT simulations and computational characterization. The geometries, electronic properties, stability studies, sensitivity, and adsorption capabilities of C18 and B9N9 counterparts towards the selected compounds confirm that the analytes interact through active cavities of the C18 and B9N9 rings of the complexes. Methods: Based on the interaction energies, the sensitivity of surfaces towards EPT, MKN, MRY, and THC analytes is observed. The interaction energy of EPT@B9N9, MKN@B9N9, MRY@B9N9, and THC@B9N9 complexes are observed − 20.40, − 19.49, − 20.07, and − 18.27 kcal/mol respectively which is more exothermic than EPT@C18, MKN@C18, MRY@C18, and THC@C18 complexes are − 16.37, − 13.97, − 13.96, and − 11.39 kcal/mol respectively. According to findings from the quantum theory of atoms in molecules (QTAIM) and the reduced density gradient (RDG), dispersion forces play a significant role in maintaining the stability of these complexes. The electronic properties including FMOs, density of states (DOS), natural bond orbitals (NBO), charge transfer, and absorption studies are carried out. In comparison of B9N9 and C18, the analyte recovery time for C18 is much shorter (9.91 × 10–11 for THC@C18) than that for B9N9 shorter recovery time value of 3.75 × 10–9 for EPT@B9N9. These results suggest that our reported sensors B9N9 and C18 make it faster to detect adsorbed molecules at room temperature. The sensor response is more prominent in B9N9 due to its fine energy gap and high adsorption energy. Consequently, it is possible to think of these monocyclic systems as a potential material for sensor applications. [ABSTRACT FROM AUTHOR]

In recent years, cell therapy has provided desirable properties for promising new drugs. Mesenchymal stem cells are promising candidates for developing genetic engineering and drug delivery strategies due to their inherent properties, including immune regulation, homing ability and tumor tropism. The therapeutic potential of mesenchymal stem cells is being investigated for cancer therapy, inflammatory and fibrotic diseases, among others. Mesenchymal stemcells are attractive cellular carriers for synthetic nanoparticles for drug delivery due to their inherent homing ability. In this review, we comprehensively discuss the various genetic and nongenetic strategies of mesenchymal stem cells and their derivatives in drug delivery, tumor therapy, immune regulation, tissue regeneration and other fields. In addition, we discuss the current limitations of stem cell therapy and the challenges in clinical translation, aiming to identify important development areas and potential future directions. [ABSTRACT FROM AUTHOR]

The construction of bicyclo[1.1.1.]pentanes (BCPs) typically require the cumbersome use of labile [1.1.1.]propellane in solution and involve multicomponent radical reactions, which commonly produce undesired by‐products that hinder the efficient construction of BCPs. In this paper, we present a catalyst‐free strategy by constructing an electron donor‐acceptor (EDA) complex utilizing the naturally electron‐deficient nature of BCP thianthrenium salt, which were irradiated with visible light to obtain trifluoromethyl‐BCP radicals through a SET process, subsequently reacted with various substituted quinoxalines. Moreover, the successful structural modification of drug molecule derivatives confirm the utility of this scheme in the field of drug discovery. [ABSTRACT FROM AUTHOR]

Tuberculosis, one of the most ancient and formidable infectious diseases, primarily arises from the pathogenic bacterium Mycobacterium tuberculosis (Mtb). Phosphoenolpyruvate carboxykinase (Pck), a potential drug target, is essential for the growth of Mtb that involves in the pathway of gluconeogenesis at the centre of phosphoenolpyruvate-pyruvate-oxaloacetate node. This study aims to understand drug-like properties of the compounds derived from artemisinin, and to investigate their inhibitory roles against Mtb. Molecular docking was performed on a set of 56 artemisinin compounds to identify their binding efficacy to the Mtb protein target. Subsequently, the selected top three complexes were subjected to molecular dynamics simulations. By the trajectory analysis, root mean square deviation and radius of gyration indicated the compactness of the systems without much fluctuation. The principal component analysis revealed that the complexes were less dynamic and energetically more favourable, and Gibbs energy landscape revealed the favourable energetic transitions between conformations. The artemisinin dimer primary alcohol holding good bioavailability scores appears highly stable in complex with Pck (MM/GBSA of −37.67 kcal/mol) that stands as a potential inhibitor of the Mtb target. However, further preclinical experiments and investigations are necessary to evaluate the intrinsic properties and to confirm effectiveness of the drug candidate. [ABSTRACT FROM AUTHOR]

This study aimed to repurpose Drug Bank Compounds against P. falciparum Dihydroorotate dehydrogenase (Pf-DHODH)a potential molecular target for antimalarial drug development due to its vital role in P. falciparum survival. Initially, the MATGEN server was used to screen drugs against Pf-DHODH (PDB ID 6GJG), followed by revalidating the results through docking by Autodock Vina through PyRx. Based on the docking results, three drugs namely, Talnifumate, Sulfaphenazole, and (3S)-N-[(2S)-1-[2-(1H-indol-3-yl)ethylamino]-1-oxopropan-2-yl]-1-(4-methoxyphenyl)-5-oxopyrrolidine-3-carboxamide—were subjected to molecular dynamics simulation for 100 ns. Molecular dynamics simulation results indicate that (3S)-N-[(2S)-1-[2-(1H-indol-3-yl)ethylamino]-1-oxopropan-2-yl]-1-(4-methoxyphenyl)-5-oxopyrrolidine-3-carboxamide— and Sulfaphenazole may target Pf-DHODH by forming a stable protein–ligand complex as they showed better free binding energy -130.58 kJ/mol, and -79.84 kJ/mol, respectively as compared to the free binding energy 116.255 kJ/mol of the reference compound; 3,6-dimethyl- ~ {N}-[4-(trifluoromethyl)phenyl]-[1,2]oxazolo[5,4-d]pyrimidin-4-amine. Although the studied compounds are drugs, still we applied Lipinski's rules and ADMET analysis that reconfirmed that these drugs have favorable drug-like properties. In conclusion, the results of the study show that Talniflumate and Sulfaphenazole may be potential antimalarial drug candidates.The derivatives of these drugs could be designed and tested to develop better drugs against Plasmodium species. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) and its downstream tropomyosin receptor kinase B (TrkB) signaling pathway play pivotal roles in the resilience and action of antidepressant drugs, making them prominent targets in psychiatric research. Oxidative stress (OS) contributes to various neurological disorders, including neurodegenerative diseases, stroke, and mental illnesses, and exacerbates the aging process. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) serves as the primary cellular defense mechanism against OS-induced brain damage. Thus, Nrf2 activation may confer endogenous neuroprotection against OS-related cellular damage; notably, the TrkB/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, stimulated by BDNF-dependent TrkB signaling, activates Nrf2 and promotes its nuclear translocation. However, insufficient neurotrophin support often leads to the downregulation of the TrkB signaling pathway in brain diseases. Thus, targeting TrkB activation and the Nrf2-ARE system is a promising therapeutic strategy for treating neurodegenerative diseases. Phytochemicals, including indole-3-carbinol (I3C) and its metabolite, diindolylmethane (DIM), exhibit neuroprotective effects through BDNF's mimetic activity; Akt phosphorylation is induced, and the antioxidant defense mechanism is activated by blocking the Nrf2-kelch-like ECH-associated protein 1 (Keap1) complex. This review emphasizes the therapeutic potential of I3C and its derivatives for concurrently activating neuronal defense mechanisms in the treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

A sensitive, easy, and low-cost method used in the determination of pure forms of losartan and mebeverine hydrochloride, also in pharmaceutical preparations with derivative spectrometry using UV-Vis technology. This method depends on measuring the first derivative of the spectrum using zero cross, peak to base line, and peak area. The linear range of concentrations used was equal to 2–14 ppm for losartan, whereas for mebeverine hydrochloride it was equal to 2–16 ppm in a mixture. For losartan, in the presence of mebeverine hydrochloride, 12 ppm by utilizing peak to baseline correlation coefficients 0.9984, 0.9994, and peak area 0.9972, whereas for mebeverine hydrochloride in the presence of losartan, 12 ppm by utilizing peak to fundamental correlation coefficients 0.9952, 0.9966, 0.9957, and peak area 0.9970, 0.9971, 0.9968, 0.9971. The limit of detection for each drug, losartan and mebeverine hydrochloride, is equal to 0.0113 ppm. The accuracy and precision of the method were estimated by calculating relative standard deviation (%RSD) values less than 3% while maintaining a recovery percentage of acceptable value. The proposed method proved effective and efficient at estimating both losartan and mebeverine hydrochloride, in the presence of the other in a mixture of the two without interference, despite the closeness of their spectral absorption peaks. There are no other more accurate methods for estimating the two in a mixture than the proposed method. The proposed method is considered one of the most direct and economical methods that do not require reagents or additional materials for conducting reactions and studying the optimal conditions for those interactions. Thus, it is considered one of the green chemistry techniques that reduce the use of chemicals and reagents in the process of estimating these drugs in a mixture and in a shorter period of time. The proposed method can be used to estimate the different properties in a mixture of the two compounds whose absorption spectra are close. [ABSTRACT FROM AUTHOR]

Antibiotic pollution has become one of the most emerging problems of the modern era. Tinidazole (TDZ) is one the most important nitroimidazole derivative drugs whose use has tremendously increased in the last few years. The proposed research work provides a good alternative cost-effective method for wastewater treatment. In the present investigation, algae were used as a photosensitizer in the treatment of the wastewater that was contaminated with antibiotic residue. The proposed research also provides the probable mechanism involved in the photodegradation of tinidazole. The different factors like concentration and pH of the test solution which play a key role in the photodegradation of drug molecules are also discussed in the present investigation. The result of this study established that the maximum degradation of drug molecules was observed at the algal concentration of 1.6 × 108 Cell/L and approximately 58% of drug molecules were degraded. This study also established that in an acidic medium ie at pH 5 the degradation occurs more efficiently. Results of the current study indicated that the use of algae-induced photodegradation of drug residue became one of the most promising routes for wastewater treatment. The results of the present study provide a new way to treat wastewater contaminated with antibiotics residue. [ABSTRACT FROM AUTHOR]

The late‐stage functionalization of active pharmaceutical ingredients is a key challenge in medicinal chemistry. Furthermore, N‐aryl triazoles and tetrazoles are important structural motifs with the potential to boost the activity of diverse drug molecules. Using easily accessible dibenzothiophenium salts for the ruthenium‐catalyzed C−H arylation, these scaffolds were introduced into a variety of bioactive compounds. Our methodology uses cost‐efficient ruthenium, KOAc as a mild base and gives access to a plethora of highly decorated triazole and tetrazole containing drug derivatives. [ABSTRACT FROM AUTHOR]

The generation of alkyl radical from C(sp3)−H substrates via hydrogen atom abstraction represents a desirable yet underexplored strategy in alkylation reaction since involving common concerns remain adequately unaddressed, such as the harsh reaction conditions, limited substrate scope, and the employment of noble metal- or photo-catalysts and stoichiometric oxidants. Here, we utilize the synergistic strategy of photoredox and hydrogen atom transfer (HAT) catalysis to accomplish a general and practical functionalization of unactived C(sp3)−H centers with broad reaction scope, high functional group compatibility, and operational simplicity. A combination of validation experiments and density functional theory reveals that the N-centered radicals, generated from free N − H bond in a stepwise electron/proton transfer event, are the key intermediates that enable an intramolecular 1,5-HAT or intermolecular HAT process for nucleophilic carbon-centered radicals formation to achieve heteroarylation, alkylation, amination, cyanation, azidation, trifluoromethylthiolation, halogenation and deuteration. The practical value of this protocol is further demonstrated by the gram-scale synthesis and the late-stage functionalization of natural products and drug derivatives. Hydrogen atom abstraction from C(sp3)−H substrates for the generation of alkyl radical represents an underexplored strategy in alkylation reactions. Here the authors describe the synergistic utilization of photoredox and hydrogen atom transfer catalysis to accomplish a general and practical functionalization of unactived C(sp3)−H centers. [ABSTRACT FROM AUTHOR]

An iron(II)‐catalyzed cascade reaction, involving cyanoalkylsulfonylation and cyclization, has been devised to enable the synthesis of functionalized sulfonylated quinolino‐quinazolinone alkyl nitriles. This three‐component radical transformation exhibits excellent chemo‐ and regioselectivity while functioning without the need for external oxidizing or reducing agents. The cost‐effectiveness of this catalytic system, together with its broad substrate application, which includes drug molecule derivatives, make this approach efficient and adaptable. [ABSTRACT FROM AUTHOR]

Fentanyl (FTN) and synthetic analogs of FTN continue to ravage populations across the globe, including in the United States where opioids are increasingly being used and abused and are causing a staggering and growing number of overdose deaths each year. This growing pandemic is worsened by the ease with which FTN can be derivatized into numerous derivatives. Understanding the chemical properties/behaviors of the FTN class of compounds is critical for developing effective chemical detection schemes using nanoparticles (NPs) to optimize important chemical interactions. Halogen bonding (XB) is an intermolecular interaction between a polarized halogen atom on a molecule and e−-rich sites on another molecule, the latter of which is present at two or more sites on most fentanyl-type structures. Density functional theory (DFT) is used to identify these XB acceptor sites on different FTN derivatives. The high toxicity of these compounds necessitated a "fragmentation" strategy where smaller, non-toxic molecules resembling parts of the opioids acted as mimics of XB acceptor sites present on intact FTN and its derivatives. DFT of the fragments' interactions informed solution measurements of XB using 19F NMR titrations as well as electrochemical measurements of XB at self-assembled monolayer (SAM)-modified electrodes featuring XB donor ligands. Gold NPs, known as monolayer-protected clusters (MPCs), were also functionalized with strong XB donor ligands and assembled into films, and their interactions with FTN "fragments" were studied using voltammetry. Ultimately, spectroscopy and TEM analysis were combined to study whole-molecule FTN interactions with the functionalized MPCs in solution. The results suggested that the strongest XB interaction site on FTN, while common to most of the drug's derivatives, is not strong enough to induce NP-aggregation detection but may be better exploited in sensing schemes involving films. [ABSTRACT FROM AUTHOR]

Alcohol is ubiquitous with unparalleled structural diversity and thus has wide applications as a native functional group in organic synthesis. It is highly prevalent among biomolecules and offers promising opportunities for the development of chemical libraries. Over the last decade, alcohol has been extensively used as an environmentally friendly chemical for numerous organic transformations. In this review, we collectively discuss the utilisation of alcohol from 2015 to 2023 in various organic transformations and their application toward intermediates of drugs, drug derivatives and natural product-like molecules. Notable features discussed are as follows: (i) sustainable approaches for C–X alkylation (X = C, N, or O) including O-phosphorylation of alcohols, (ii) newer strategies using methanol as a methylating reagent, (iii) allylation of alkenes and alkynes including allylic trifluoromethylations, (iv) alkenylation of N-heterocycles, ketones, sulfones, and ylides towards the synthesis of drug-like molecules, (v) cyclisation and annulation to pharmaceutically active molecules, and (vi) coupling of alcohols with aryl halides or triflates, aryl cyanide and olefins to access drug-like molecules. We summarise the synthesis of over 100 drugs via several approaches, where alcohol was used as one of the potential coupling partners. Additionally, a library of molecules consisting over 60 fatty acids or steroid motifs is documented for late-stage functionalisation including the challenges and opportunities for harnessing alcohols as renewable resources. [ABSTRACT FROM AUTHOR]

Background: The identification of novel therapeutic strategies for ovarian cancer (OC), the most lethal gynecological neoplasm, is of utmost urgency. Here, we have tested the effectiveness of the compound 2c (4-hydroxy-2,6-bis(4-nitrobenzylidene)cyclohexanone 2). 2c interferes with the cysteine-dependent deubiquitinating enzyme (DUB) UCHL5, thus affecting the ubiquitin-proteasome-dependent degradation of proteins. Methods: 2c phenotypic/molecular effects were studied in two OC 2D/3D culture models and in a mouse xenograft model. Furthermore, we propose an in silico model of 2c interaction with DUB-UCHL5. Finally, we have tested the effect of 2c conjugated to several linkers to generate 2c/derivatives usable for improved drug delivery. Results: 2c effectively impairs the OC cell line and primary tumor cell viability in both 2D and 3D conditions. The effectiveness is confirmed in a xenograft mouse model of OC. We show that 2c impairs proteasome activity and triggers apoptosis, most likely by interacting with DUB-UCHL5. We also propose a mechanism for the interaction with DUB-UCHL5 via an in silico evaluation of the enzyme-inhibitor complex. 2c also reduces cell growth by down-regulating the level of the transcription factor E2F1. Eventually, 2c activity is often retained after the conjugation with linkers. Conclusion: Our data strongly support the potential therapeutic value of 2c/derivatives in OC. [ABSTRACT FROM AUTHOR]

The rapid assembly of valuable cyclic amine architectures in a single step from simple precursors has been recognized as an ideal platform in term of efficiency and sustainability. Although a vast number of studies regarding cyclic amine synthesis has been reported, new synthetic disconnection approaches are still high in demand. Herein, we report a catalytic radical‐polar crossover cycloaddition to cyclic amine synthesis triggered from primary sulfonamide under photoredox condition. This newly developed disconnection, comparable to established synthetic approaches, will allow to construct β, β‐disubstituted cyclic amine and β‐monosubstituted cyclic amine derivatives efficiently. This study highlights the unique utility of primary sulfonamide as a bifunctional reagent, which acts as a radical precursor and a nucleophile. The open‐shell methodology demonstrates broad tolerance to various functional groups, drug derivatives and natural products in an economically and sustainable fashion. [ABSTRACT FROM AUTHOR]

Despite the importance of heteroatom‐substituted cyclopropane derivatives in drug design and organic synthesis, cyclopropanethiols remain critically underexplored. Inspired by the wide use of the Newman‐Kwart rearrangement to access valuable thiophenols from phenol feedstocks, we report the development of a photocatalytic approach for efficient ambient temperature aliphatic O‐ to S‐rearrangement on tertiary cyclopropanol derivatives. After demonstrating that a range of cyclopropanethiols—that are difficult to access by other methods—can be obtained with this strategy, we show that these rearranged products can be easily hydrolyzed and further derivatized. We conclude this study with mechanistic findings that enabled an initial extension of this approach toward other classes of aliphatic alcohols. [ABSTRACT FROM AUTHOR]

We report a highly enantioselective intermolecular C−H bond silylation catalyzed by a phosphoramidite‐ligated iridium catalyst. Under reagent‐controlled protocols, propargylsilanes resulting from C(sp3)−H functionalization, as well the regioisomeric and synthetically versatile allenylsilanes, could be obtained with excellent levels of enantioselectivity and good to excellent control of propargyl/allenyl selectivity. In the case of unsymmetrical dialkyl acetylenes, good to excellent selectivity for functionalization at the less‐hindered site was also observed. A variety of electrophilic silyl sources (R3SiOTf and R3SiNTf2), either commercial or in situ‐generated, were used as the silylation reagents, and a broad range of simple and functionalized alkynes, including aryl alkyl acetylenes, dialkyl acetylenes, 1,3‐enynes, and drug derivatives were successfully employed as substrates. Detailed mechanistic experiments and DFT calculations suggest that an η3‐propargyl/allenyl Ir intermediate is generated upon π‐complexation‐assisted deprotonation and undergoes outer‐sphere attack by the electrophilic silylating reagent to give propargylic silanes, with the latter step identified as the enantiodetermining step. [ABSTRACT FROM AUTHOR]

Quinoline and its derivatives are a family with unique medicinal properties, including antibacterial effects. It was assumed that the four quinoline derivatives 1, 2, 3 and 4 had significant activity against pathogenic bacteria. These compounds were synthesized and characterized by TLC, IR, 1H NMR, and 13C NMR analyses. The biological activity of compounds was determined as inhibition zone (IZ) in mm. For compound 1 IZ was 19 ± 0.22 against Klebsiella pneumoniae, IZ was 18 ± 0.22 against Bacillus subtilis, and IZ was 17 ± 0.22 against Staphylococcus aureus. 2 displayed IZ of 18 ± 0.22 against both Klebsiella pneumoniae and Bacillus subtilis. 3 showed IZ of 17 ± 0.22 against Staphylococcus aureus. 4 displayed IZ of 21 ± 0.22, thus showing a higher inhibitory activity against Escherichia coli, than ciprofloxacin. These results demonstrate the potential of the synthesized compounds to work as antibacterial drugs against these strains by inhibiting or deactivating the target proteins. [ABSTRACT FROM AUTHOR]

In this study, different heterocyclic entities consisting of tyrosine amino acid and triazine ring were designed based on the structure of fingolimod, the first oral drug for multiple sclerosis (MS). Interaction of these compounds with S1P1 and S1P3, as two involving targets for fingolimod, was evaluated utilizing molecular docking and then the designed compounds were synthesized and evaluated in the terms of red blood cell and T-lymphocyte depletion in comparison to fingolimod. The 4-aminopyridine substituted derivative (8a) showed low binding energy with the active site of S1P1 (−9.4 kcal/mol) and higher binding energy (−5.87 kcal/mol) with the active site of S1P3. Also, in pharmacological studies, this compound was able to reduce white blood cells better than fingolimod and did not show destructive effects on red blood cells, unlike fingolimod. [ABSTRACT FROM AUTHOR]

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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]

Chemical transformation triggered by an electron donor–acceptor (EDA) complex without the addition of an exogenous stoichiometric electron donor/acceptor is rare. Herein, we report such a process to access 2,3-difunctionalized pyridines from readily available N-aminopyridiniums (1) and activated alkenes (2) promoted by visible light. This procedure offered multi-substituted pyridines in satisfactory yields at room temperature with broad functional group tolerance. The reaction can be easily performed on a gram scale without the loss of yield. The modification of bioactive molecules including derivatives of clinical drugs and natural products was demonstrated. Mechanistic studies and DFT calculations indicated that the formal [3 + 2] cycloaddition and aza-Michael addition between 1 and 2 generated tetrahydropyrazolo[1,5-a]pyridine and a new pyridinium salt, respectively. These two intermediates formed an EDA complex, which under visible-light illumination, triggered the following single electron transfer (SET)/N–N bond cleavage/C–N bond formation cascade process with high atom economy. [ABSTRACT FROM AUTHOR]

Inhibiting the activity of intestinal α-glucosidase is considered an effective approach for treating type II diabetes mellitus (T2DM). In this study, we employed an in vitro enzymatic synthesis approach to synthesize four derivatives of natural products (NPs) for the discovery of therapeutic drugs for T2DM. Network pharmacology analysis revealed that the betulinic acid derivative P3 exerted its effects in the treatment of T2DM through multiple targets. Neuroactive ligand–receptor interaction and the calcium signaling pathway were identified as key signaling pathways involved in the therapeutic action of compound P3 in T2DM. The results of molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations indicate that compound P3 exhibits a more stable binding interaction and lower binding energy (−41.237 kcal/mol) with α-glucosidase compared to acarbose. In addition, compound P3 demonstrates excellent characteristics in various pharmacokinetic prediction models. Therefore, P3 holds promise as a lead compound for the development of drugs for T2DM and warrants further exploration. Finally, we performed site-directed mutagenesis to achieve targeted synthesis of betulinic acid derivative. This work demonstrates a practical strategy of discovering novel anti-hyperglycemic drugs from derivatives of NPs synthesized through in vitro enzymatic synthesis technology, providing potential insights into compound P3 as a lead compound for anti-hyperglycemic drug development. [ABSTRACT FROM AUTHOR]

An operationally simple anhydrous carbene insertion reaction to construct DNA‐encoded libraries (DEL) is reported. The developed reaction employs visible light photolysis of diazo compounds and Reversible Adsorption to Solid Support (RASS) strategy. From readily available amines, alcohols, phenols, and carboxylic acids, a variety of high‐value molecules, including useful unnatural amino acids, ethers, and esters, promising clinical drug derivatives, and bioactive molecules have been constructed. [ABSTRACT FROM AUTHOR]

We herein describe a protocol to synthesize trifluoromethylated alkyl boronates from alkenes by the mutual activation of the Togni II and the bis(catecholato)diboron reagents in the absence of any catalyst and additives. This reaction enables synthesizing a series of trifluoromethylated alkyl boronates using unactivated alkenes, including natural products and drug derivatives, in a regioselective manner. Moreover, the synthetic utility of the boronic ester present in the product allows access to a range of trifluoromethyl containing compounds. The radical trapping and gas detection experiments reveal that the more Lewis acidic diboron reagent determines the rapid formation of trifluoromethyl and boron centered radicals. [ABSTRACT FROM AUTHOR]

Thermodynamic properties of molecules provide fundamental information for binding in fragment‐based drug discovery programs and for understanding complex interactions. Experimental measurements of some thermodynamic properties are not always feasible. Quantum mechanical methods and group contribution methods are the major toolboxes to obtain some theoretical quantities. In drug discovery and development, computational studies can reduce the costs and risks of bringing a new medicine to market. Computational methods have been widely used to optimize promising new ligands by estimating their binding affinity to proteins using the thermodynamic ligand binding parameters (Gibbs energy, enthalpy, entropy, and heat capacity). In this article, the relationship between molecular descriptors and quantum chemical properties, such as the Gibbs free energy (ΔG kJ mol−1) and enthalpy of formation (ΔHf kJ mol−1) of 2‐phenylindole derivatives as anticancer drugs is studied. These properties were calculated at the DFT‐B3LYP/6‐311G (d,p) level of quantum chemistry by Gaussian 09 software. Molecular descriptors were calculated by Dragon 5.4 software, and the stepwise multiple linear regression (MLR) and the Genetic algorithm (GA) techniques were used to select the best descriptors and build QSPR models. To evaluate the predictive ability of developed quantitative structure‐property relationship (QSPR) models, different internal and external validation methods were adopted. The predictive powers of the models were found to be satisfactory. The models revealed that 3D matrix‐based descriptors (H3D, SEig) are useful to predict the Gibbs free energy and enthalpy of formation of the investigated compounds respectively. [ABSTRACT FROM AUTHOR]

Piperine is a plant-derived promising piperamide candidate isolated from the black pepper (Piper nigrum L.). In the last few years, this natural botanical product and its derivatives have aroused much attention for their comprehensive biological activities, including not only medical but also agricultural bioactivities. In order to achieve sustainable development and improve survival conditions, looking for environmentally friendly pesticides with low toxicity and residue is an extremely urgent challenge. Fortunately, plant-derived pesticides are rising like a shining star, guiding us in the direction of development in pesticidal research. In the present review, the recent progress in the biological activities, mechanisms of action, and structural modifications of piperine and its derivatives from 2020 to 2023 are summarized. The structure-activity relationships were analyzed in order to pave the way for future development and utilization of piperine and its derivatives as potent drugs and pesticides for improving the local economic development. [ABSTRACT FROM AUTHOR]

An iron‐catalyzed, visible light‐driven, dioxygen mediated decarboxylative oxygenation of carboxylic acids is disclosed. The catalytic system based on naturally existing Mohr salt and simple di(2‐picolyl)amine ligand is readily available and inexpensive. The applicability of the method was demonstrated through the efficient and selective synthesis of a range of ketones, aldehydes and amides including drug derivatives. Based on experimental investigations, a hypothetical mechanism was proposed. [ABSTRACT FROM AUTHOR]

Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT2A receptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT2A receptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT1A and 5-HT2C receptors, and with neurotrophin receptors (e.g., tropomyosin receptor kinase B). These interactions contribute to the complexity of their effects on perception, mood, and cognition. Moreover, as psychedelic research advances, there is an increasing interest in developing nonhallucinogenic derivatives of these drugs to create safer and more targeted medications for psychiatric disorders by removing the hallucinogenic properties while retaining the potential therapeutic benefits. These nonhallucinogenic derivatives would offer patients therapeutic advantages without the intense psychedelic experience, potentially reducing the risks of adverse reactions. Finally, we discuss the potential of psychedelics as substrates for post-translational modification of proteins as part of their mechanism of action. [ABSTRACT FROM AUTHOR]

A convenient method has been proposed for the preparation of new derivatives of adamantine-based drugs, such as memantine and rimantadine. The synthesis was performed by functionalization of amino-group of memantine and rimantadine by ipso-substitution of cyano-group at C5 position of 1,2,4-triazine scaffold with the corresponding aminoadamantane moieties with subsequent aza-Diels–Alder transformation of 1,2,4-triazine cycle into pyridine one in some cases. [ABSTRACT FROM AUTHOR]

C-aryl glycosides are an important kind of carbohydrate derivatives for drug discovery, due to their distinctive attributes of resistance to hydrolysis from enzymes. Herein, C-aryl glycosylation was established for the synthesis of 2-sulfur C-aryl glycals and 1,2-dihydrobenzofuran-fused C-aryl glycosides via interrupted Pummerer process, featured with sulfonium-tethered [3,3]-sigmatropic rearrangement between sulfoxide glycals and phenols. This protocol offers a broad substrate scope with diverse glycosyl and phenols. Dapagliflozin, Empagliflozin, and Ipragliflozin analogs were straightforward achieved, respectively. [ABSTRACT FROM AUTHOR]

In the current paper, the adiabatic ionization potentials (AIP) for 29 hydantoin derivatives and hydantoin‐based drugs such as allantoin, phenytoin, mephenytoin, nilutamide, iprodione, nitrofurantoin, and ethotoin were calculated using the double hybrid ωB97XD density functional theory (DFT) in coupling with 6‐311+G(2df,2p) basis set at the B3LYP/6‐31+G(d,p) optimized geometry. The neutral and cationic radicals of the examined species were firstly optimized using the B3LYP/6‐31+G(d,p) level. Final energies were improved by single point calculation using 16 different DFT methods such as B3LYP, ωB97, B97D, TPSSTPSS, M06‐2X, ..., and so forth, with 6‐311+G(2df,2p) basis. Statistical tools such as root mean square error (RMSE) was used to examine the accuracy of the DFT method with respect to the standard reference AIP values. These standard references were calculated, for 12 hydantoin derivatives with less than nine non‐hydrogen atoms, by taking the average values of the AIP computed using the G4, G3B3, and CBS‐QBS methods. The vertical ionization potentials (VIPs), the vertical electron affinity (VEA), and global quantum parameters such as electrophilicity and nucleophilicity of the 29 molecules were also calculated. Substitution effect on the AIP, VIP, VEA, fundamental gap, electrophilicity, and nucleophilicity of the species under probe was studied and discussed. The results reveal that substitution of electron withdrawing group (EWG) raises the AIP and VIP, electrophilicity, and the fundamental gap, while substitution of electron donating group (EDG) raises the VEA and the nucleophilicity. Furthermore, the condensed Fukui functions were used to identify the active centers for nucleophilic, electrophilic, and free radical attacks. [ABSTRACT FROM AUTHOR]

The liposome particle size is an important parameter because it strongly affects content release from liposomes as a result of different bilayer curvatures and lipid packing. Earlier, we developed pH-responsive polysaccharide-derivative-modified liposomes that induced content release from the liposomes under weakly acidic conditions. However, the liposome used in previous studies size was adjusted to 100–200 nm. The liposome size effects on their pH-responsive properties were unclear. For this study, we controlled the polysaccharide-derivative-modified liposome size by extrusion through polycarbonate membranes having different pore sizes. The obtained liposomes exhibited different average diameters, in which the diameters mostly corresponded to the pore sizes of polycarbonate membranes used for extrusion. The amounts of polysaccharide derivatives per lipid were identical irrespective of the liposome size. Introduction of cholesterol within the liposomal lipid components suppressed the size increase in these liposomes for at least three weeks. These liposomes were stable at neutral pH, whereas the content release from liposomes was induced at weakly acidic pH. Smaller liposomes exhibited highly acidic pH-responsive content release compared with those from large liposomes. However, liposomes with 50 mol% cholesterol were not able to induce content release even under acidic conditions. These results suggest that control of the liposome size and cholesterol content is important for preparing stable liposomes at physiological conditions and for preparing highly pH-responsive liposomes for drug delivery applications. [ABSTRACT FROM AUTHOR]

Herein, an electrochemically driven NiH‐catalyzed reductive coupling of alkyl halides and alkyl alkenes for the construction of Csp3−Csp3 bonds is firstly reported. Notably, alkyl halides serve dual function as coupling substrates and as hydrogen sources to generate NiH species under electrochemical conditions. The tunable nature of this reaction is realized by introducing an intramolecular coordinating group to the substrate, where the product can be easily adjusted to give the desired branched products. The method proceeds under mild conditions, exhibits a broad substrate scope, and affords moderate to excellent yields with over 70 examples, including late‐stage modification of natural products and drug derivatives. Mechanistic insights offer evidence for an electrochemically driven coupling process. The sp3‐carbon‐halogen bonds can be activated through single electron transfer (SET) by the nickel catalyst in its low valence state, generated by cathodic reduction, and the generation of NiH species from alkyl halides is pivotal to this transformation. [ABSTRACT FROM AUTHOR]

Viral infections in humans are responsible for fatalities worldwide and contribute to the incidence of various human ailments. Controllable targeted medicine delivery against many illnesses, including viral infection, may be significantly aided by using bacteria and bacteria-derived products. They may accumulate in diseased tissues despite physical obstacles, where they can launch antiviral immunity. The ability to genetically and chemically modify them means that vaccinations against viral infections may be manufactured and delivered to affected tissues more safely and effectively. The objective of this study is to provide an overview of the latest advancements in the field of utilizing bacteria and bacterial derivatives as carriers for administering medication to treat viral diseases such as SARS-CoV-2, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, human papillomavirus, influenza, and Ebola virus. [ABSTRACT FROM AUTHOR]

Polycaprolactone (PCL) is polymer of 21st centuries. PCL is a biodegradable and biocompatible polymer used for various healthcare applications. This review explores the properties, synthesis, and processing of PCL. The use of PCL polymer for nanoparticles (NPs), microparticles, films, and fibers offers several advantages for biomedical applications. The review highlights the potential of PCL‐based materials for tissue engineering, drug delivery, wound healing, and implantable medical devices. We also critically analyzed challenges in PCL‐based materials and the strategies used to overcome for successful translation into clinical applications. Overall, this review provides a comprehensive overview of PCL as a valuable biomaterial for healthcare applications. [ABSTRACT FROM AUTHOR]

Oxidized methylcytidines 5-hydroxymethyl-2′deoxycytidine (5hmdC) and 5-formy-2′deoxycytidine (5fdC) are deaminated by cytidine deaminase (CDA) into genome-toxic variants of uridine, triggering DNA damage and cell death. These compounds are promising chemotherapeutic agents for cancer cells that are resistant to pyrimidine derivative drugs, such as decitabine and cytarabine, which are inactivated by CDA. In our study, we found that cancer cells infected with mycoplasma exhibited a markedly increased sensitivity to 5hmdC and 5fdC, which was independent of CDA expression of cancer cells. In vitro biochemical assay showed that the homologous CDA protein from mycoplasma was capable of deaminating 5hmdC and 5fdC into their uridine form. Moreover, mycoplasma infection increased the sensitivity of cancer cells to 5hmdC and 5fdC, whereas administration of Tetrahydrouridine (THU) attenuated this effect, suggesting that mycoplasma CDA confers a similar effect as human CDA. As mycoplasma infection occurs in many primary tumors, our findings suggest that intratumoral microbes could enhance the tumor-killing effect and expand the utility of oxidized methylcytidines in cancer treatment. [Display omitted] • Tumor killing effect of 5hmdC and 5fdC is enhanced by mycoplasma infection. • Mycoplasma cytidine deaminase deaminates 5hmdC and 5fdC into cytotoxic agents. • Intratumoral microbes may expand the utility of 5hmdC and 5fdC in cancer treatment. [ABSTRACT FROM AUTHOR]

Conventional dihydroxylation of alkenes is one of the most powerful synthetic tools for delivering two hydroxyl groups at vicinal positions. The direct formation of 1,3-diols remains a formidable challenge, yet dihydroxyl groups are broadly present in bioactive compounds, and are currently only available synthetically via multiple steps. The oxidative ring-opening of arylcyclopropanes has been demonstrated to access various 1,3-difunctionalized chemicals, but no 1,3-diols have been directly synthesized owing to their inherently high proclivity to become further oxidized. Herein, we report a facile and efficient strategy to 1,3-diols involving controlled electrochemical C–C bond cleavage of arylcyclopropanes with H2O as the ultimately green hydroxyl source. Moreover, this protocol stands out with its high atom economy, broad substrate scope and excellent functional group tolerance, and hence is amenable to the synthesis of complex natural products and drug derivatives. [ABSTRACT FROM AUTHOR]