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Methanol is gaining popularity as a transfer-hydrogenating agent in catalytic reduction reactions because of its bulk-scale production and inexpensive nature. Current research interests include the utilization of methanol as a safe and sustainable hydrogen source for chemical synthesis and drug development. In particular, the chemoselective reduction of α,β-unsaturated ketones is of great interest because of their prevalence in many natural products. We investigated the potential application of acridine-derived SNS-Ru pincer complexes in methanol activation for chemoselective reduction of chalcones. Our developed catalytic system showed broad substrate tolerance, including substrates containing reducible functional groups. Control experiments and postsynthetic applications are also highlighted. [ABSTRACT FROM AUTHOR]

Two new complexes of Pd(II), [Pd(L1)Cl]Cl (Pd1) and [Pd(L2)Cl]Cl (Pd2), (where L1 = N2,N6-bis(5-methylthiazol-2-yl)pyridine-2,6-dicarboxamide and L2 = N2,N6-di(benzo[d]thiazol-2-yl)pyridine-2.6-dicarboxamide) were synthesized. Characterization of the complexes was performed using elemental analysis, IR, 1H NMR spectroscopy and MALDI-TOF mass spectrometry. The nucleophilic substitution reactions of complexes with L -Methionine (L -Met), L -Cysteine (L -Cys) and guanosine-5′-monophosphate (5′-GMP) were studied by stopped-flow method at physiological conditions (pH = 7.2 and 37 °C). Complex Pd1 was more reactive than Pd2 in all studied reactions, while the order of reactivity of the selected ligands was: L -Met > L -Cys > 5′-GMP. The interaction of complexes with calf thymus-DNA (CT-DNA) was studied by Uv–Vis absorption and fluorescence emission spectroscopy. Competitive binding studies with intercalative agent ethidium bromide (EB) and minor groove binder Hoechst 33258 were performed as well. Both complexes interacted with DNA through intercalation and minor groove binding, where the latter was preferred. Additionally, the interaction of Pd1 and Pd2 complexes with human serum albumin (HSA) was studied employing fluorescence quenching spectroscopy. The results indicate a moderate binding affinity of complexes, with slightly stronger binding of the Pd1. Fluorescence competition experiments with site-markers (eosin Y and ibuprofen) for HSA were used to locate the binding site of Pd1 to the HSA. Additionally, the interaction with DNA and HSA was studied by molecular docking and the revealed results were in good agreement with the experimentally obtained ones. Pd1 complex exhibited cytotoxicity toward human (HCT116) and mouse cell lines (CT26) of colorectal cancer, mouse (4T1) and human (MDA-MB468) breast cancer lines and non-cancerous mouse mesenchymal stem cells (mMSC). In addition, Pd1 complex demonstrated significant selectivity towards cancer cells over non-cancerous mMSC, indicating a high potential to eliminate malignant cells without affecting normal cells. It induced apoptosis in CT26 cells, effectively arrested the cell cycle in the S phase, and selectively down-regulated cyclin D and cyclin E. Moreover, it can alter the expression of cell cycle regulators by increasing p21 and decreasing p-AKT. These findings confirm its ability to disrupt key tumor cell survival signals and suggest that the Pd1 complex is a potent candidate for effective cancer treatment. [ABSTRACT FROM AUTHOR]

Direct functionalization of alkenes with C(sp3)–H substrates offers unique opportunities for the rapid construction of pharmaceuticals and natural products. Although significant progress has been made over the past decades, the development of green, high step-economy methods to achieve these transformations under mild conditions without the need for pre-functionalization of C(sp3)–H bonds remains a substantial challenge. Therefore, the pursuit of such methodologies is highly desirable. Recently, the direct activation of C(sp3)–H bonds via photocatalytic hydrogen atom transfer (HAT), especially from unactivated alkanes, has shown great promise. Given the potential of this approach to generate a wide range of pharmaceutically relevant compounds, this review highlights the recent advancements in the direct functionalization of alkenes through photocatalytic HAT from C(sp3)–H compounds, as well as their applications in the synthesis and diversification of drugs, natural products, and bioactive molecules, aiming to provide medicinal chemists with a practical set of tools. [ABSTRACT FROM AUTHOR]

A regioselective novel one-pot synthesis of heterocyclic purine derivative antiviral agent Ganciclovir in which initially guanine is treated with acetic anhydride in the presence of iodine (5%) to get diacetyl guanine intermediate, which undergoes in situ N-alkylation with AMDP in presence of catalytic acidic Amberlite IR-120 to get N-alkylated intermediate and finally deacetylation to get pure regioselective Ganciclovir, which is commercially viable and eco-friendly. We developed one-pot synthesis of antiviral drug Ganciclovir. Initially, Guanine is treated with acetic anhydride and iodine to yield diacetyl guanine 3. This intermediate then reacted with AMDP in the presence of acidic Amberlite IR-120 to obtain compound 5. Finally, deacetylation yields Ganciclovir 1, a commercially viable and eco-friendly process. [ABSTRACT FROM AUTHOR]

Memantine hydrochloride, a non‐competitive antagonist of NMDA‐type glutamate receptors, is known to suppress the progression of symptoms in Alzheimer's disease. Possessing a characteristic adamantane skeleton as its core structure and an amino group at the bridgehead position, memantine was synthesized starting from acenaphthene. The synthesis involved nucleus hydrogenation of acenaphthene to perhydroacenaphthene, skeletal rearrangement of perhydroacenaphthene, nitration of 1,3‐dimethyladamantane, and reduction of the nitro groups to an amino group. In each step, continuous flow reactions were investigated to achieve continuous manufacturing of memantine. [ABSTRACT FROM AUTHOR]

We disclose a mediated electrochemical [2+2+2] annulation of alkynes with nitriles, forming substituted pyridines in a single step from low‐cost, readily available starting materials. The combination of electrochemistry and a triarylamine redox mediator obviates the requirements of transition metals and additional oxidants. Besides the formation of diarylpyridine moieties via the homocoupling of two identical alkynes, the heterocoupling of two different alkynes depending on their electronic nature is possible, highlighting the unprecedented control of chemoselectivity in this catalytic [2+2+2] process. Mechanistic investigations like cyclic voltammetry and crossover experiments combined with DFT calculations indicate the initial oxidation of an alkyne as the key step leading to the formation of a vinyl radical cation intermediate. The utilization of continuous flow technology proved instrumental for an efficient process scale‐up. The utility of the products is exemplified by the synthesis of π‐extended molecules, being relevant for material or drug synthesis. [ABSTRACT FROM AUTHOR]

Electrically controlled droplet manipulation is attractive for lots of applications ranging from material synthesis and drug delivery. However, the present techniques using bulky and expensive power supplies to generate high‐voltage electrical signals are easy to cause electrode electrolysis, bubble formation in buffer solution, and are incapable for point‐of‐care testing. Herein, a novel and portable electrical method for self‐powered emulsion droplet core coalescence and release based on triboelectric nanogenerator (TENG) is presented. The electrical signal with a 2.25 kV open‐voltage and a 35 µA short‐circuit current can be conveniently generated via frictional electrification effect, and the harmful electrochemical reaction in solutions can be avoided. The high transient pulse voltage and stable sinusoidal signal between two electrodes in microfluidic device can generate a strong electric field, which causes apparent Maxwell electrical stresses at droplet interfaces and subsequently promotes the core coalescence and release of double‐emulsions. By adjusting the voltage magnitude, the core coalescence and release behaviors of double‐emulsion droplets can be controllably achieved, followed by the synthesis copper‐based metal–organic framework (Cu‐MOF) nanoparticles. Thus, this portable, effective and self‐powered droplet manipulation technique can be attractive for those droplet‐based applications. [ABSTRACT FROM AUTHOR]

Halogenation reactions are a vital area of study for the pharmaceutical industry. The study of the reaction conditions along with the reactors and their scale-up is a thrust area in drug synthesis and manufacturing. There is a shift in the research community towards accommodating renewable energy sources which has driven scientists to include energy sources that are sustainable and aid in making the overall process efficient. This review provides a comprehensive overview of the challenges in selecting the best catalyst, light source and reaction conditions for the fluorination, chlorination and bromination reactions. This paper goes a step further to explain the photoreactors’ design and modelling as well as the scale-up of the same. Overall, it provides a comprehensive view of diverse scientific areas, from halogenation in drug synthesis to the potential of photochemical batch and flow approaches in halogenation reactions. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cell‐based immunotherapy has received much attention in recent years. However, its practical application is still suffering from the decreased function and inadequate infiltration of NK cells in the immunosuppressive microenvironment of solid tumors. Herein, we construct light‐responsive porphyrin Fe array‐armed NK cells (denoted as NK@p‐Fe) for cell behavior modulation via bioorthogonal catalysis. By installing cholesterol‐modified porphyrin Fe molecules on the NK cell surface, a catalytic array with light‐harvesting capabilities is formed. This functionality transforms NK cells into cellular factories capable of catalyzing the production of active agents in a light‐controlled manner. NK@p‐Fe can generate the active antineoplastic drug doxorubicin through bioorthogonal reactions to enhance the cytotoxic function of NK cells. Beyond drug synthesis, NK@p‐Fe can also bioorthogonally catalyze the production of the FDA‐approved immune agonist imiquimod (IMQ). The activated immune agonist plays a dual role, inducing dendritic cell maturation for NK cell activation and reshaping the tumor immunosuppressive microenvironment for NK cell infiltration. This work represents a paradigm for the modulation of adoptive cell behaviors to boost cancer immunotherapy by bioorthogonal catalysis. [ABSTRACT FROM AUTHOR]

A highly diastereoselective total synthesis of Eliglustat has been accomplished starting from a readily available D‐serine. This novel route involves a four‐step telescoped process to afford the keto intermediate (4) in 74% overall yield. The diastereoselective reduction of 4 using sodium borohydride provides the alcohol, a key intermediate 5, with excellent selectivity (>99 dr) and yield (95%). The total synthesis of Eliglustat from D‐serine has been accomplished in ten steps with an overall yield of 21%. This process not only gives a desirable yield but also avoids the use of hazardous conditions. [ABSTRACT FROM AUTHOR]

The integration of trifluoromethyl groups and three-dimensional quaternary carbon moieties into organic molecules has emerged as a prominent strategy in medicinal chemistry to augment drug efficacy. Although trifluoromethyl (hetero)aromatic amines and derivatives are prevalent frameworks in pharmaceuticals, the development of trifluoromethyl-embedded, intricately structured alkyl amine scaffolds for medicinal research remains a significant challenge. Herein, we present a metallaphotoredox multicomponent amination strategy employing 3,3,3-trifluoropropene, nitroarenes, tertiary alkylamines, and carboxylic acids. This synthetic pathway offers notable advantages, including the accessibility and cost-effectiveness of starting materials, high levels of chemo- and regioselectivity, and modularity. Furthermore, this approach enables the synthesis of a broad spectrum of aniline compounds featuring both trifluoromethyl group and distal quaternary carbon motifs along the aliphatic chains. The accelerated access to such elaborate N-trifluoroalkyl anilines likely involves three sequential radical-mediated coupling events, providing insightful implications for the retrosynthesis of potential compounds in organic synthesis and drug discovery. The trifluoromethyl group can confer advantageous properties to biologically relevant molecules, but methods for its incorporation into aliphatic carbons that are more embedded within the core of the structure are less available. Here, the authors present a multicomponent coupling to synthesize carbon skeletons with a branched trifluoromethyl group via iridium metallaphotoredox catalysis. [ABSTRACT FROM AUTHOR]

Herein, we have reported a sustainable and chemo‐selective strategy for the synthesis of functionalized branched alcohols. A commercially available catalytic system does not need any special ligand and liberated water and hydrogen as side products. A series of alkyl primary alcohols (C4–C10), including methanol, were tolerated in good to high yield. Sequential transformations to substituted pyrroles, chromenes and synthesis of donepezil drug were obtained (>57 entries). Preliminary mechanistic investigations were performed to understand the catalytic pathways. [ABSTRACT FROM AUTHOR]

The field of drug delivery has significantly advanced tumor therapy, yet challenges such as the predictability of treatment outcomes and the real‐time monitoring of tumor progression, such as recurrence or metastasis. Luminescent metal–organic frameworks (L‐MOFs) are a promising solution to overcome these issues. This review offers a comprehensive exploration of the design and synthesis of L‐MOFs, presenting their crucial optical properties. The review highlights the pivotal role of L‐MOFs in enabling precision medicine for tumor treatment driven by their performance. Through strategically harnessing light‐manipulated metal–organic frameworks (MOFs), real‐time therapeutic monitoring and precise spatiotemporal control in tumor treatment can be achieved. Moreover, this review meticulously examines the influence of photomanipulating MOFs on in situ drug synthesis, introducing the catalytic role in light‐manipulated gas therapy. Additionally, the role of L‐MOFs as gene therapy vectors that utilize light to trigger gene expression responses is also comprehensively explored in the article, aiming to highlight their role in enabling tumor therapy through gene therapy. The review concludes by proposing an artificial intelligence (AI)‐mediated blueprint for tumor treatment with L‐MOFs, aiming to pave the way for innovative approaches through light manipulation. [ABSTRACT FROM AUTHOR]

Fungi generate a diverse array of bioactive compounds with significant pharmaceutical applications. However, the chemical diversity of natural products in fungi remains largely unexplored. Here, we present a paradigm for specifically discovering diverse and bioactive compounds from fungi by integrating genome mining with building block molecular network and coculture analysis. Through pangenome and sequence similarity network analysis, we identified a rare type I polyketide enzyme from Penicillium sp. ZJUT-34. Subsequent building block molecular network and coculture strategy led to the identification and isolation of a pair of novel polyketides, (±)-peniphenone E [(±)−1], three known polyketides (2–4), and three precursor compounds (5–7) from a combined culture of Penicillium sp. ZJUT-34 and Penicillium sp. ZJUT23. Their structures were established through extensive spectroscopic analysis, including NMR and HRESIMS. Chiral HPLC separation of compound 1 yielded a pair of enantiomers (+)−1 and (−)−1, with their absolute configurations determined using calculated ECD methods. Compound (±)−1 is notable for its unprecedented structure, featuring a unique 2-methyl-hexenyl-3-one moiety fused with a polyketide clavatol core. We proposed a hypothetical biosynthetic pathway for (±)−1. Furthermore, compounds 2, 5, and 6 exhibited strong antioxidant activity, whereas (−)−1, (+)−1, 3, and four exhibited moderate antioxidant activity compared to the positive control, ascorbic acid. Our research demonstrates a pioneering strategy for uncovering novel polyketides by merging genome mining, metabolomics, and cocultivation methods. This approach addresses the challenge of discovering natural compounds produced by rare biosynthetic enzymes that are often silent under conventional conditions due to gene regulation. IMPORTANCE Polyketides, particularly those with complex structures, are crucial in drug development and synthesis. This study introduces a novel approach to discover new polyketides by integrating genomics, metabolomics, and cocultivation strategies. By combining genome mining, building block molecular networks, and coculturing techniques, we identified and isolated a unique polyketide, (±)-peniphenone E, along with three known polyketides and three precursor compounds from Penicillium sp. ZJUT-34 and Penicillium sp. ZJUT23. This approach highlights the potential of using combined strategies to explore fungal chemical diversity and discover novel bioactive compounds. The successful identification of (±)-peniphenone E, with its distinctive structure, demonstrates the effectiveness of this integrated method in enhancing natural product discovery and underscores the value of innovative approaches in natural product research. [ABSTRACT FROM AUTHOR]

Chiral phenylalanine derivatives are important raw materials and building blocks for the synthesis of peptides and drug molecules. Enantiomerically pure D/L‐3‐pyridyl‐ and phenylalanine has shown wide application potential in the synthesis of various drug intermediates. This article focuses on two synthetic routes from different feedstocks. The first approach is an Erlenmeyer–Plöchl route study using N‐acetylglycine as starting material, whereas the second is an alkylation route study using diethyl acetamidomalonate as starting material. The key step is the resolution of N‐acetamido‐alanine esters using different quantities of fairly inexpensive Protamex proteinase to obtain pure enantiomeric D/L‐3‐pyridyl‐ and substituted phenylalanine or its derivative, with the ee value and purity of all products exceeding 99%. The different chiral arylalanine derivatives that can be prepared using the above two methods have good versatility. [ABSTRACT FROM AUTHOR]

The design and synthesis of antiviral compounds were guided by computationally predicted data against highly conserved non-structural proteins (Nsps) of the SARS-CoV-2 coronavirus. Chromenephenylmethanone-1 (CPM-1), a novel biphenylpyran (BPP), was selected from a unique natural product library based on in silico docking scores to coronavirus Nsps with high specificity to the methyltransferase protein (2′-O-MTase, Nsp10–16), which is responsible for viral mRNA maturation and host innate immune response evasion. To target the 2′-O-MTase, CPM-1, along with intermediate BPP regioisomers, tetrahydrophenylmethanones (TPMs), were synthesized and structurally validated via nuclear magnetic resonance (NMR) data and DP4+ structure probability analyses. To investigate the activity of these BPPs, the following in vitro assays were conducted: SARS-CoV-2 inhibition, biochemical target validation, mutagenicity, and cytotoxicity. CPM-1 possessed notable activity against SARS-CoV-2 with 98.9% inhibition at 10 µM and an EC50 of 7.65 µM, as well as inhibition of SARS-CoV-2's 2′-O-MTase (expressed and purified) with an IC50 of 1.5 ± 0.2 µM. In addition, CPM-1 revealed no cytotoxicity (CC50 of >100 µM) or mutagenicity (no frameshift or base-pair mutations). This study demonstrates the potential of computational modeling for the discovery of natural product prototypes followed by the design and synthesis of drug leads to inhibit the SARS-CoV-2 2′-O-MTase. [ABSTRACT FROM AUTHOR]

The reproducibility of chemical reactions, when obtaining protocols from literature or databases, is highly challenging for academicians, industry professionals and even now for the machine learning process. To synthesize the organic molecule under the photochemical condition, several years for the reaction optimization, highly skilled manpower, long reaction time etc. are needed, resulting in non-affordability and slow down the research and development. Herein, we have introduced the DigiChemTree backed with the artificial intelligence to auto-optimize the photochemical reaction parameter and synthesizing the on demand library of the molecules in fast manner. Newly, auto-generated digital code was further tested for the late stage functionalization of the various active pharmaceutical ingredient. Light-induced reactions of diazo compounds have become crucial in organic synthesis and drug discovery, however, optimization of reaction conditions is still very time-consuming. Here, the authors develop a DigiChemTree platform using artificial intelligence to auto-optimize the photochemical reaction parameters and rapidly synthesize an on-demand library of molecules. [ABSTRACT FROM AUTHOR]

Hydrogenation plays an important role in the production of bulk and fine chemicals. In the present work, the hydrogenation process of 1-cyanocyclohexaneacetic acid (1-CA), a key intermediate in the chemo-enzymatic synthesis of the antiepileptic drug gabapentin, was investigated. The catalysts were screened, the operating parameters for the 1-CA hydrogenation were determined by response surface methodology, and the effects of biological impurities on the reaction and catalysts were investigated. The reaction temperature, reaction solution pH and reaction time were identified as the main factors for hydrogenation by single-factor experiments. Under the optimal reaction conditions: reaction temperature 110 °C, solution pH 12.33, reaction time 3.74 h, hydrogen pressure 2 MPa and stirring speed 500 rpm, the substrate conversion reached 100%, and the total product yield reached 96.40%, which was very close to the prediction (96.88%). It was demonstrated that biological impurities greatly affect the reaction rate of hydrogenation, as well as the activity and reusability of the catalyst, in which protein impurities lead to catalyst deactivation through cumulative deposition on the catalyst surface and within the pores. [ABSTRACT FROM AUTHOR]

Objective: The aims of this article are to review the clinical aspects of rozanolixizumab, to describe clinical trial results that led to the drug's approval, and to examine the impact on patient care to aid clinical decision making. Data Sources: A PubMed search was conducted using the terms Rystiggo ™, rozanolixizumab, rozanolixizumab therapy, and myasthenia gravis. The most recent prescribing information was also used for information relating to the drug and for identification of pertinent studies. Study Selection/Data Extraction: Phase I, II, and III randomized controlled trials were all eligible for inclusion. Meeting abstracts and articles focusing on the use of rozanolixizumab or any indication other than generalized myasthenia gravis were excluded from this article. Data Synthesis: Food and Drug Administration approval of rozanolixizumab is based on the phase III MycarinG study in patients with generalized myasthenia gravis. A phase II trial explored initial clinical efficacy and safety pertaining to the dose and frequency of rozanolixizumab across 2 treatment periods in patients with moderate to severe myasthenia gravis. Relevance to Patient Care and Clinical Practice in Comparison to Existing Agents: Rozanolixizumab is the first therapy approved to treat patients positive for both types of antibodies, anti-acetylcholine receptor or anti-muscle-specific tyrosine kinase, in generalized myasthenia gravis. Conclusion/Relevance: The approval of rozanolixizumab represents an advancement in therapy for generalized myasthenia gravis. The provision of individualized, targeted, and well-tolerated treatment is valuable for the patients whose myasthenia gravis is not well controlled and who are seeking a medication with a rapid onset of action to improve their symptoms and overall quality of life. [ABSTRACT FROM AUTHOR]

The efficient preparation of long-chain amines via a one-step transfer-hydrogenation/reductive-amination reaction (THRA) of polyenals has been achieved. This strategy, which combines transfer hydrogenation and reductive amination, significantly enhances the synthetic efficiency of amino compounds. Additionally, this protocol offers a practical method for carbon-chain elongation/amination to construct long-chain amino compounds. The reaction system exhibits remarkable versatility in substrate scope using a non-noble ruthenium catalyst with formate and isopropanol as hydrogen sources, making it an appealing method for drug synthesis and molecular modification. [ABSTRACT FROM AUTHOR]

Dichloromethane, as a readily available and inexpensive C1 synthon is proposed as a powerful building block for cyclopropanation of alkenes under mild conditions. Herein, we report a highly efficient and versatile dual photoredox system, involving a nickel aminopyridine coordination complex and a photocatalyst, for the cyclopropanation of aromatic olefins using dichloromethane, under visible‐light irradiation. The cyclopropanation protocol has been successfully applied at gram scale. Mechanistic studies suggest a Ni(II) pyridyl radical complex as the key intermediate for the homolytic cleavage of the Csp3−Cl bond, generating a chloromethyl radical that is captured by the olefin coupling partner. Our findings also highlight the versatility of this methodology. By directing the radical/polar crossover process, we were able to selectively drive the reaction towards either the formation of cyclopropyl derivatives or the corresponding non‐cyclic alkyl chloride products. The methodology also successfully apply to geminal dichloroalkanes, including the formation of spiro[2,2] compounds. Moreover, our methodology extends to the synthesis of deuterium‐labelled cyclopropanes, demonstrating its utility in isotopic labelling and broadening its applicability in chemical synthesis and drug development. [ABSTRACT FROM AUTHOR]

Methods for producing drugs directly at the cancer site, particularly using bioorthogonal metal catalysts, are being explored to mitigate the side effects of therapy. Albumin‐based artificial metalloenzymes (ArMs) catalyze reactions in living mice while protecting the catalyst in the hydrophobic pocket. Here, we describe the in situ preparation and application of biocompatible tumor‐targeting ArMs using circulating albumin, which is abundant in the bloodstream. The ArM was formed using blood albumin through the intravenous injection of ruthenium conjugated with an albumin‐binding ligand; the tumor‐targeting unit was conjugated to the ArM using its catalytic activity, and the ArM was transported to the cancer site. The delivered ArM catalyzed a second tagging reaction of the proapoptotic peptide on the cancer surface, successfully suppressing cancer proliferation. This approach, which efficiently leveraged the persisting reactivity twice in vivo, holds promise for future in vivo metal‐catalyzed drug synthesis utilizing endogenous albumin. [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]

Chiral tertiary alcohols are an important structural motif, however, the general and efficient methodologies for their synthesis are less reported. Herein, we report a Ni(ІІ)-catalyzed asymmetric alkenylation and arylation of aryl ketones with organoborons under air via a 1,5-metalate shift strategy to obtain chiral tertiary allylic alcohols and diaryl alcohols. The reaction demonstrates good functional group tolerance and delivers chiral tertiary alcohols with good to excellent results. Furthermore, this method can be applied to the late-stage modification of drugs and the efficient synthesis of natural products. Notably, the reaction proceeds through an outer-sphere mechanism. The Ni(II) complex functions both as a Lewis acid to activate the ketone and create a chiral environment, and as coordination bridge linking the ketone and the organoboron-derived "ate" complex, facilitating the 1,5-metalate shift without forming a C-Ni bond. This approach contrasts with traditional transition metal-catalyzed nucleophilic addition reactions that involve carbon-metal bond formation. Chiral tertiary alcohols are an important structural motif, but the general methodologies for the synthesis are less reported. Herein, the authors report a Ni(ІІ)-catalyzed asymmetric alkenylation and arylation of aryl ketones with organoborons under air via a 1,5-metalate shift to obtain chiral tertiary allylic alcohols and diaryl alcohols. [ABSTRACT FROM AUTHOR]

Site‐selective amination of N‐heterocycles is an interesting topic in organic synthesis and drug discovery. We herein present a method for the vicarious‐type nucleophilic amination of azine N‐oxides and cyclic iminoamides using iminyl anions, readily generated from organic azides under basic conditions. The plausible reaction mechanism involving nucleophilic aromatic substitution by iminyl anions is elucidated by a series of mechanistic investigations. [ABSTRACT FROM AUTHOR]

AbstractIn recent years, the inadequacy and high costs of current cancer treatment drugs have led to an increase in research focused on the design and synthesis of new compounds with potential applications in this field and the evaluation of their anticancer properties using in silico methods. For this purpose, four novel heterocyclic compounds (6–9) were synthesized and characterized using spectroscopic techniques. The DFT approach and B3LYP/6-311G(d,p) basis set were used to compare theoretical data with experimental ones and to obtain optimized geometries. It was observed that experimental and theoretical data were in harmony. In silico techniques were used to investigate the potential of synthesized compounds as drug candidates. ADMEt results have shown that all synthesized compounds have Lipinski’s rule of five which has searched criteria in drug candidates. Molecular docking studies were also performed against cancer-related proteins. The highest docking score between 2XIR protein and compound 8 was found to be −11.7 kcal/mol, while the lowest was −8.2 kcal/mol between 1MP8 protein and compound 9. To do meaningful comparisons standard drugs were also used in Molecular Docking studies. It was observed that all synthesized molecules had higher docking scores than standard drugs except ifebemtinib. It can be suggested that based on ADMET and molecular docking studies compound 8 has the potential to be a drug candidate after further investigations such as in vitro, in silico, etc., have been performed in this area. [ABSTRACT FROM AUTHOR]

In this study, a Ni‐based metal‐organic framework (MOF), Ni‐MOF, was synthesized from a mixture of Ni(OAc)2 ⋅ 4H2O, a dicarboxylate, 4,4'‐(1,3,4‐oxadiazole‐2,5‐diyl)dibenzoate (oxdz2−), and a bis(tridentate) ligand, (N,N',N",N"'‐tetrakis(2‐pyridylmethyl)‐1,4‐diaminoxylylene) (tpxn), under ambient conditions using greener solvents in 12 h. The framework was well‐characterized using several analytical techniques. The highly crystalline Ni‐MOF exhibited remarkable polarizing traits with significant uptake of CO2 and water vapor up to 10.53 cm3 g−1 and 290 cm3 g−1, respectively, at 298 K. The isosteric heat of adsorption between Ni‐MOF and CO2 at zero loading was calculated to be 32.43 kJ mol−1. Furthermore, utilizing its CO2‐philic and catalytic features, Ni‐MOF was employed as an excellent heterogeneous catalyst (2.5 mol%) along with very low concentration of TBAB (0.02 mmol) as a co‐catalyst for the synthesis of oxazolidinones via a standard three‐component reaction among an epoxide, a substituted aniline, and carbon dioxide under solvent‐free conditions. A wide range of oxazolidinones including three bioactive derivatives was synthesized using both diverse epoxides and aniline derivatives to demonstrate the substrate scope. The catalyst was proved to be recyclable, reusable, and stable for multiple cycles, without leaching of the metal from it. The mechanistic insights revealed that Ni‐MOF polarizes all three reactants to catalyze the oxazolidinone formation. [ABSTRACT FROM AUTHOR]

The excessive and prolonged use of antibiotics contributes to the emergence of drug‐resistant S. aureus strains and potential dysbacteriosis‐related diseases, necessitating the exploration of alternative therapeutic approaches. Herein, we present a light‐activated nanocatalyst for synthesizing in situ antimicrobials through photoredox‐catalytic click reaction, achieving precise, site‐directed elimination of S. aureus skin infections. Methylene blue (MB), a commercially available photosensitizer, was encapsulated within the CuII‐based metal–organic framework, MOF‐199, and further enveloped with Pluronic F‐127 to create the light‐responsive nanocatalyst MB@PMOF. Upon exposure to red light, MB participates in a photoredox‐catalytic cycle, driven by the 1,3,5‐benzenetricarboxylic carboxylate salts (BTC−) ligand presented in the structure of MOF‐199. This light‐activated MB then catalyzes the reduction of CuII to CuI through a single‐electron transfer (SET) process, efficiently initiating the click reaction to form active antimicrobial agents under physiological conditions. Both in vitro and in vivo results demonstrated the effectiveness of MB@PMOF‐catalyzed drug synthesis in inhibiting S. aureus, including their methicillin‐resistant strains, thereby accelerating skin healing in severe bacterial infections. This study introduces a novel design paradigm for controlled, on‐site drug synthesis, offering a promising alternative to realize precise treatment of bacterial infections without undesirable side effects. [ABSTRACT FROM AUTHOR]

Sulfonamides have been played a critical role in the history of medicinal chemistry development for decades. In particular, sulfonamides display a broad spectrum in pharmaceutical drugs synthesis. This review presents a short discussion of the microwave‐assisted synthetic approaches, enhancement of sulfonamides moieties and their pharmacological applications are being discussed. During the past few decades, microwave‐assisted technology in organic synthesis has been highlighted to introducing ‐SO2NH functional group in the multi synthetic routes for the development of bioactive molecule and also assisted in the estimation of their credible mechanistic routes for the reactions. [ABSTRACT FROM AUTHOR]

A diastereoselective synthesis for the preparation of (R)‐methyl pipecolate and dextro‐erythrophacetoperane, analogs of methylphenidate, drugs used to treat attention deficit hyperactivity disorder, is reported. The key steps involve a high diastereoselective ring‐closing reaction via enolate formation and a diastereoselective ketone reduction reaction. The total synthesis of these valuable drugs could be obtained in only 5 and 8 steps, respectively, starting from (S)‐(−)‐methyl benzylamine. [ABSTRACT FROM AUTHOR]

Deuteration has emerged as a significant method for investigating kinetic isotope effects in chemical reactions. In recent years, research on deuteration has revealed that this reaction often alters the pharmacokinetic or toxicological properties of drug molecules, thereby enhancing their therapeutic effect. Therefore, deuteration is considered as a potential avenue for drug research direction. Since the approval of the first deuterated drug, "deutetrabenazine," by the American Food and Drug Administration (FDA) in 2017, deuteration has been applied in the development of a variety of novel drugs. Research on deuteration technology has matured with the publication of numerous deuteration strategies. This article reviews recently reported strategies for late‐stage selective deuteration, discusses the challenges associated with current deuteration strategies, and presents future prospects for the synthesis of deuterated drugs. [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]

The synthesis of peptide drugs has become facile with the use of supports that enable easy separation of the growing peptide. Peptide synthesis on insoluble supports typically employs excess reagents to enhance reaction efficiency and faces challenges during intramolecular cyclization. A non‐crosslinked soluble polystyrene support is reported herein that improves cyclization efficiency on the support by using spacers. The support efficiency is illustrated by synthesizing octreotide drug in a scalable manner by on‐support cyclization. The methodology drastically reduces the reagent waste, raw‐material cost, and solvent requirement. The support can also be recovered and re‐used up to 3 times making this a very sustainable method. [ABSTRACT FROM AUTHOR]

Bis‐heterocycles were synthesized via a consecutive one‐pot process by a Groebke‐Blackburn‐Bienaymé reaction (GBB‐3CR) followed by Copper‐catalyzed Alkyne‐Azide Cycloaddition (CuAAC) assisted by alternative sustainable energies (ASE) such as ultrasonic and mechanical. These efficient and convergent strategies allowed the in situ generation of complex azides functionalized with imidazo[1,2‐a]pyridines (IMPs), which was used as a synthetic platform. The target molecules contain two privileged scaffolds in medicinal chemistry: IMPs and the heterocyclic bioisostere of trans‐amide bond, the 1,4‐disubstituted 1H‐1,2,3‐triazoles (1,4‐DS‐1,2,3‐Ts). [ABSTRACT FROM AUTHOR]

(R)-3-Isobutylglutarate monoamide (R-IBM) is a key intermediate in the synthesis of the analgesic drug pregabalin. Recently, the imidase BpIH derived from Burkholderia phytofirmans was identified as a promising catalyst for the industrial production of R-IBM. Notably, this catalyst has the distinct advantage of achieving a 100% theoretical yield from 3-isobutyl glutarimide (IBI). In this study, homology modeling and structure alignment techniques were used to determine the substrate binding pocket of BpIH. Semi-rational design was used to analyze the amino acid residue conservation in the binding pocket region of BpIH. Interestingly, mutations of several low-conserved amino acid located 6–9 Å from the substrate significantly enhanced the catalytic activity of BpIH. Among them, the triple mutant Y37FH133NS226I (YHS-I) showed approximately a fivefold increase in enzyme activity and a significantly improved catalytic efficiency (kcat/Km). Under the same reaction time and conditions, YHS-I successfully converted IBI into R-IBM with a conversion rate of 88.87%, with an enantiomeric excess (ee) of the product exceeding 99.9%. In comparison, wild-type BpIH had a conversion rate of only 38.15%. Molecular dynamics and docking results indicated that YHS-I had higher rigidity around the mutation sites. The synergistic substitutions of Y37F, H133N, and S226I altered the interaction network within the mutation site, enhancing the protein's affinity for the substrate and improving catalytic efficiency. Key points: • 100% theoretical yield of R-IBM by BpIH compared with 50% by resolution • Semi-rational design of BpIH based on conservativity with homologous enzymes • Mutant with enzyme activity of sixfold and product ee value of 99.9% [ABSTRACT FROM AUTHOR]

The photochemistry of EDA complexes is initiated from a groundstate associate with a biomolecule capable of intermolecular electron transfer by channelling chemical synthesis via a specific radical-based mechanistic pathway. Herein, we activate the innovative cascade mode of EDA complex photoexcitation for nitroreduction in aqueous media using charge transfer interactions between a sole donor and multiple acceptors (ArNO2, ArNO, and ArNHOH·glycine adduct). A triplet-state quenching experiment, UV-vis analysis, NMR titration, and preliminary kinetic investigation verified the rationality and feasibility of the mechanism. With successful applications of this cascaded system in arylamine compounds and commercially available drug synthesis (61 examples), these achievements highlight the attractiveness, usefulness, and effectiveness of this protocol. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Unsymmetrical diarylamines are crucial components in many pharmaceuticals and functional materials. In this study, we introduce an efficient Chan‐Lam cross‐coupling method that utilizes phenylboronic acids and aryl azides as coupling agents in a redox‐neutral environment, enabled by a synergistic nickel/photoredox catalytic system. This approach leverages a proton‐coupled electron transfer mechanism to bypass the typical nitrene pathway associated with aryl azides, which is prone to intramolecular rearrangement, C—H amination, and reductive hydrogenation. Notably, our method exhibits broad compatibility with a variety of functional groups, including those derived from pharmaceuticals, demonstrating its versatile potential in organic synthesis and drug modification. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: In this paper, the difunctionalizative perfluoroalkyloximation of alkenes has been developed for the first time. This photochemical method allows for the synthesis of various perfluoroalkyl ethanone oximes with excellent regioselectivity and good functional group tolerance. Our method employs the most common perfluoroalkyl source, perfluoroalkyl iodides, as Rf reagents. Besides long‐chain perfluoroalkyl groups, this approach could be extended to incorporating additional groups, including trifluoromethyl, difluoromethyl, sulfonyl, and malonate, selectively into olefins, resulting in a range of β‐substituted ethanone oximes. Notably, the potential of this method in the Fukuyama indole synthesis, generating novel 2‐perfluoroalkylated 3‐(α‐oximidobenzyl)indoles via a radical cascade mechanism with 2‐vinylphenylacryloyl isocyanate as the radical acceptor, presents a compelling avenue for drug synthesis. The protocol is efficient, scalable, and useful for late‐stage modification of bioactive molecules. [ABSTRACT FROM AUTHOR]

Atropisomers have attracted a great deal of attention lately due to their numerous applications in organic synthesis and to their employment in drug discovery. However, the synthetic arsenal at our disposal with which to access them remains limited. The research described herein is two‐pronged; we both demonstrate the use of MCR chemistry as a synthetic strategy for the de novo synthesis of a class of atropisomers having high barriers to rotation with the simultaneous insertion of multiple chiral elements and we study these unprecedented molecular systems by employing a combination of crystallography, NMR and DFT calculations. By fully exploiting the synthetic capabilities of our chemistry, we have been able to monitor a range of different types of interaction, i. e. π‐π, CH–π, heteroatom‐π and CD–π, in order to conduct structure‐property studies. The results could be applied both to atroposelective synthesis and in drug discovery. [ABSTRACT FROM AUTHOR]

An improved, scalable, industrially feasible telescopic process for multigram synthesis of highly commercialized antidepressant drug, moclobemide has been developed. Unlike the conventional approaches, this process enjoys the privilege of being an economical, operationally simple, effectively scalable, and quantitative method for the synthesis of amide‐containing drug moclobemide, showcasing easy isolation and purification without the aid of column chromatography. An environmentally benign reagent combination of TBN and NHS very effectively converts the acyl source, 4‐chlorobenzaldehyde into its N‐hydroxysuccinimide ester intermediate, which simply affords the drug molecule after nucleophilic substitution with the amine source. The synthetic process has successfully been scaled‐up upto ~145 g scale with 75 % overall yield and >95 % first crop HPLC purity. [ABSTRACT FROM AUTHOR]

Nucleoside phosphorylases (NPs) are pivotal enzymes in the salvage pathway, catalyzing the reversible phosphorolysis of nucleosides to produce nucleobases and α-D-ribose 1-phosphate. Due to their efficiency in catalyzing nucleoside synthesis from purine or pyrimidine bases, these enzymes hold significant industrial importance in the production of nucleoside-based drugs. Given that the thermodynamic equilibrium for purine NPs (PNPs) is favorable for nucleoside synthesis—unlike pyrimidine NPs (PyNPs, UP, and TP)—multi-enzymatic systems combining PNPs with PyNPs, UPs, or TPs are commonly employed in the synthesis of nucleoside analogs. In this study, we report the first development of two engineered bifunctional fusion enzymes, created through the genetic fusion of purine nucleoside phosphorylase I (PNP I) and thymidine phosphorylase (TP) from Thermus thermophilus. These fusion constructs, PNP I/TP-His and TP/PNP I-His, provide an innovative one-pot, single-step alternative to traditional multi-enzymatic synthesis approaches. Interestingly, both fusion enzymes retain phosphorolytic activity for both purine and pyrimidine nucleosides, demonstrating significant activity at elevated temperatures (60–90 °C) and within a pH range of 6–8. Additionally, both enzymes exhibit high thermal stability, maintaining approximately 80–100% of their activity when incubated at 60–80 °C over extended periods. Furthermore, the transglycosylation capabilities of the fusion enzymes were explored, demonstrating successful catalysis between purine (2′-deoxy)ribonucleosides and pyrimidine bases, and vice versa. To optimize reaction conditions, the effects of pH and temperature on transglycosylation activity were systematically examined. Finally, as a proof of concept, these fusion enzymes were successfully employed in the synthesis of various purine and pyrimidine ribonucleoside and 2′-deoxyribonucleoside analogs, underscoring their potential as versatile biocatalysts in nucleoside-based drug synthesis. [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. [ABSTRACT FROM AUTHOR]

Potential genotoxic impurities in medications are an increasing concern in the pharmaceutical industry and regulatory bodies because of the risk of human carcinogenesis. To prevent the emergence of these impurities, it is crucial to carefully examine not only the final product but also the intermediates and key starting material (KSM) used in drug synthesis. During the related substances analysis of KSM of Famotidine, an unknown impurity in the range of 0.5–1.0% was found prompting the need for isolation and characterization due to the possibility of its to infiltrate into the final product. In this study, the impurity was isolated and characterized as 5-(2-chloroethyl)-3,3-dimethyl-3,4-dihydro-2H-1,2,4,6-thiatriazine 1,1-dioxide using multiple instrumental analysis, uncovering a structural alert that raises concern. Considering the potential impact of impurity on human health, an in silico genotoxicity assessment was established using Derek and Sarah tool in accordance with ICH M7 guideline. Furthermore, molecular docking and molecular dynamics simulation were performed to evaluate the specific interaction of the impurity with DNA. The findings reveal consistent interaction of the impurity with the dG-rich region of the DNA duplex and binding at the minor groove. Both in silico prediction and molecular dynamic study confirmed the genotoxic character of the impurity. The newly discovered impurity in famotidine has not been reported previously, and there is currently no analytical method available for its identification and control. A highly sensitive HPLC-UV method was developed and validated in accordance with ICH requirements, enabling quantification of the impurity at trace level in famotidine ensuring its safe release. [ABSTRACT FROM AUTHOR]

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AbstractProblem StatementMethodResultsDiscussionPublic Statement of RelevanceAmong individuals aged 12 years or older, 14.3% (40.0 million) reporting the use of an illicit drug in the previous year. Given the prevalence of drug abuse, it is increasingly important to determine effective screening practices, treatment procedures, and best practices among various subpopulations to identify drug use-related consequences. The DAST is one of the most commonly used and accurate drug screening tests.This psychometric synthesis of four versions of the Drug Abuse Screening Test (DAST-10, DAST-20, DAST-28, DAST-A) provided aggregated evidence from 346 articles over 40 years of published literature for score reliability, structure, diagnostic, and convergent validity, and descriptive statistics, all with the goal of informing counseling and medical practice and research.Results indicated adequate internal consistency (α = 0.81–0.84 across all four versions) and mostly medium to large effect size convergent correlations with comparison measures. Aggregated diagnostic validity data indicate optimal cutoff scores of 7 for DAST-10, 8 for DAST-20, 10 for DAST-28, and 6 for DAST-A.The DAST-10 appears the best choice for practical and psychometric reasons. Additional studies of the various DAST versions are needed to expand use across participant demographics.Drug use continues to be a societal problem and mental health practitioners need effective screening practices, treatment procedures, and best practices among various subpopulations to identify drug use-related consequences. This study synthesized 40 years of research on the four versions of the Drug Abuse Screening Test (DAST-10, DAST-20, DAST-28, DAST-A) and found acceptable levels of score reliability and validity for screening purposes. [ABSTRACT FROM AUTHOR]

Sulfinamidines are promising aza‐SIV chiral building blocks in asymmetric synthesis and drug discovery. However, no report has documented their enantioselective synthesis. Here we present an enantioselective synthesis of sulfinamidines via electrophilic amination of sulfenamides using an enantiopure N−H oxaziridine. The resulting enantiomerically enriched primary sulfinamidines are configurationally stable at 90 °C in solution and show remarkable stability against organic acids and bases under non‐aqueous conditions. We also demonstrate a one‐pot, three‐component, enantioselective synthesis of sulfinamides using N−H oxaziridine reagents. [ABSTRACT FROM AUTHOR]

In this communication, we designed a highly selective camphor sulfonyl functionalized crown-ether-tethered calix[4]arene-derived organocatalyst for asymmetric Strecker reaction to provide the desired cyano adducts in high yields (∼99.9% yield) and enantioselectivities (up to 99.3% ee). Furthermore, 2 step facile syntheses of the antiplatelet drug (S)-clopidogrel exemplify the potential of this method for the preparation of commercial compounds. [ABSTRACT FROM AUTHOR]

The reagent system based on the combined use of Et3SiH/I2 acts as an efficient N-glycosidation promoter for the synthesis of natural and sugar-modified nucleosides. An analysis of reaction stereoselectivity in the absence of C2-positioned stereodirecting groups revealed high selectivity with six-membered substrates, depending on the nucleophilic character of the nucleobase or based on anomerization reactions. The synthetic utility of the Et3SiH/I2-mediated N-glycosidation reaction was highlighted by its use in the synthesis of the investigational drug apricitabine. [ABSTRACT FROM AUTHOR]

During gliotoxin biosynthesis in fungi, the cytochrome P450 GliF enzyme catalyzes an unusual C–N ring-closure step while also an aromatic ring is hydroxylated in the same reaction cycle, which may have relevance to drug synthesis reactions in biotechnology. However, as the details of the reaction mechanism are still controversial, no applications have been developed yet. To resolve the mechanism of gliotoxin biosynthesis and gain insight into the steps leading to ring-closure, we ran a combination of molecular dynamics and density functional theory calculations on the structure and reactivity of P450 GliF and tested a range of possible reaction mechanisms, pathways and models. The calculations show that, rather than hydrogen atom transfer from the substrate to Compound I, an initial proton transfer transition state is followed by a fast electron transfer en route to the radical intermediate, and hence a non-synchronous hydrogen atom abstraction takes place. The radical intermediate then reacts by OH rebound to the aromatic ring to form a biradical in the substrate that, through ring-closure between the radical centers, gives gliotoxin products. Interestingly, the structure and energetics of the reaction mechanisms appear little affected by the addition of polar groups to the model and hence we predict that the reaction can be catalyzed by other P450 isozymes that also bind the same substrate. Alternative pathways, such as a pathway starting with an electrophilic attack on the arene to form an epoxide, are high in energy and are ruled out. [ABSTRACT FROM AUTHOR]

Phenolic compounds have long captivated the interest of organic synthesis, particularly in their quest for selective hydroxylation of arenes using H2O as a hydroxyl source. However, the inherent high reactivity and low redox potential of phenols often lead to undesirable overoxidation byproducts. To address this challenge, herein, we develop an electrophotochemical approach, finetuning substrate oxidative potential and enabling para-selective hydroxylation of anilides. This method showcases versatility, accommodating a wide array of substrates, while revealing high regional selectivity and compatibility with diverse functional groups. Moreover, the protocol allows facile late-stage functionalization of biologically active molecules. Mechanistic investigations demonstrate the activation of anilides by the excited state photocatalyst, effectively decreasing their oxidative potential and enhancing regional selectivity during hydroxylation. By using this protocol, important drug molecules such as Paracetamol, Fenretinide, Practolol, and AM404 could be synthesized, demonstrating the applicability of this approach in drug synthesis and late-stage functionalization. Phenolic compounds have long captivated the interest of organic synthesis, particularly in their quest for selective hydroxylation of arenes using H2O as a hydroxyl source but the inherent high reactivity and low redox potential of phenols often lead to undesirable overoxidation byproducts. Here the authors develop an electrophotochemical approach, finetuning substrate oxidative potential and enabling para-selective hydroxylation of anilides. [ABSTRACT FROM AUTHOR]