Bioisosteric Replacement Research Articles

Catalytic Intermolecular Asymmetric [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes: Practical Synthesis of Enantioenriched Highly Substituted Bicyclo[2.1.1]hexanes.

The high percentage of sp3-hybridized carbons and the presence of chiral carbon centers could contribute to increased molecular complexity, enhancing the likelihood of clinical success of drug candidates. Three-dimensional (3D) bridged motifs have recently garnered significant interest in medicinal chemistry. Bicyclo[2.1.1]hexanes (BCHs) are emerging 3D benzene bioisosteres, but the synthesis of chiral, highly substituted BCHs has been underexplored. Herein, we disclose the Lewis acid-catalyzed asymmetric intermolecular [2π + 2σ] cycloaddition of bicyclo[1.1.0]butanes with coumarins, 2-pyrone, or chromenes to access diverse enantioenriched 1,2,3,4-tetrasubstituted BCHs bearing vicinal tertiary-quaternary stereocenters. The key to success is the introduction of chiral bisoxazoline ligands to effectively suppress the side reactions, inhibit significant racemic background reactions, and fine-tune the reactivity and regio-, enantio-, and diastereoselectivities of the reactions. The resulting BCHs hold significant potential as benzene bioisosteres in the synthesis of chiral BCHex-Sonidegib and BCHex-BMS-202, mimicking the anticancer drug Sonidegib and the PD-1/PD-L1 inhibitor BMS-202, respectively. The outcome highlights the positive impact of bioisosteric replacement on physicochemical properties, while maintaining comparable antitumor activity to their aryl-containing counterparts.

Discovery of novel pyrazoline insecticides.

The pyrazoline insecticides, invented by Philips Duphar in the 1970s, provide excellent control of lepidopterans and coleopterans and introduced a novel mode of action (MoA) as sodium-channel-blocking insecticides, but were not commercialized due to unacceptable persistence. This MoA is less explored, with only two successfully commercialized insecticides derived from the pyrazoline class - the oxadiazine indoxacarb from FMC (developed by DuPont) and the semicarbazone metaflumizone, co-developed by BASF and Nihon Nohyaku. The design and synthesis of novel pyrazoline insecticides with improved biological efficacy and favorable environmental fate profile are described. Their structures are confirmed by proton nuclear magnetic resonance (1H-NMR) and liquid chromatography-mass spectrometry (LC-MS). Bioassay studies confirmed the insecticidal efficacy of the synthesized compounds against four key species: cotton boll weevil, tobacco budworm, diamondback moth and southern armyworm. Environmental fate profiles of a few representatives were evaluated, and MoA studies confirm that the MoA of these newly synthesized analogs (voltage-gated sodium channel block) is preserved. We used a chemistry-driven approach to explore position 5 on the pyrazoline core and a computationally-driven approach for bio-isosteric replacement of the aryl amide, leading to two novel pyrazoline sub-classes with improved insecticidal activities and favorable environmental fate profiles compared to PH 60-41 (the Philips Duphar compound). The MoA of these novel sub-classes was also confirmed as block of voltage-dependent sodium channels. © 2024 Society of Chemical Industry.

Discovery of a new eugenol-benznidazole hybrid active against different evolutive stages of Trypanosoma cruzi

Chagas disease (CD) is a life-threatening illness caused by the protozoan Trypanosoma cruzi and there are only two drugs currently available for pharmacotherapy of this neglected infection (benznidazole and nifurtimox). Their limited efficacy in chronic phase of the disease, problems of toxicity and the growing resistance by the protozoan are directly associated to high rates of drug discontinuation by the patients. In the context of the search for new trypanocidal drug candidates, our group has been working with the chemical manipulation of eugenol to obtain new agents active against T. cruzi and promising results have been achieved. In this work we designed molecular hybrids between eugenol and benznidazole (BZN) by performing a bioisosteric replacement between the nitroimidazole ring of BZN by the eugenol or analogues nucleus in nitrated or non-nitrated forms. The obtained compounds were initially evaluated against epimastigote stages of T. cruzi for selecting the most active ones. Three hybrids (8, 10 and 15) showed activity against this evolutive stage and the most promising was eugenol nitro derivative 8 (IC50: 24.7 µM) that showed a similar potential than BZN (IC50: 29.9 µM). Compounds 8, 10 and 15 were then evaluated against infective trypomastigote and intracellular amastigote forms of T. cruzi and the cytotoxicity of them was investigated against healthy Vero and H9c2 cells. The nitro derivative 8 was once again the most promising compound against trypomastigote (IC50: 1.8 µM) and amastigote (IC50: 1.6 µM) forms, with selectivity indices greater than 63 considering both health cells evaluated. This compound was more active than BZN, that showed IC50 values of 6.1 µM (trypomastigotes) and 3.1 µM (amastigotes) and showed the most significant effect in reducing the infection rate and accumulation of parasites in infected cells. Calculated logP values suggest that the higher lipophilicity of derivative 8 (clogP: 3.25) in relation to BZN (clogP: 0.77) may be correlated to a greater ability of this eugenol derivative to cross the membranes of infected cells. Finally, to try understand the possible mode of action for compound 8, we have evaluated three important targets of the parasite (T. cruzi nitroreductase type I – TcNRT, trypanothione reductase – TR and mitochondrial membrane depolarization), but none of these metabolic pathways seem to be related to the mechanism of action of this compound. All in vitro assays employed the T. cruzi Y strain which exhibits partial resistance to benznidazole and these results indicate compound 8 as a new promising hit for the development of drug candidates to treat CD.

Structure-property Relationships Reported for the New Drugs Approved in 2023.

Drug-like properties play pivotal roles in drug adsorption, distribution, metabolism, excretion, and toxicity. Therefore, efficiently optimizing these properties is essential for the successful development of novel therapeutics. Understanding the structure-property relationships of clinically approved drugs can provide valuable insights for drug design and optimization strategies. Among the new drugs approved in 2023, which include 31 small-molecule drugs in the US, the structureproperty relationships of nine drugs were compiled from the medicinal chemistry literature, in which detailed information on pharmacokinetic and/or physicochemical properties was reported not only for the final drug but also for its key analogs generated during drug development. The structure- property relationships of nine newly approved drugs are summarized, including three kinase inhibitors and three G-protein-coupled receptor antagonists. Several optimization strategies, such as bioisosteric replacement and steric handle installation, have successfully produced clinical candidates with enhanced physicochemical and pharmacokinetic properties. The summarized structure- property relationships demonstrate how appropriate structural modifications can effectively improve overall drug-like properties. The ongoing exploration of structure-property relationships of clinically approved drugs is expected to offer valuable guidance for developing future drugs.

3,3-Difluorooxetane-A Versatile Functional Group for Bioisosteric Replacements in Drug Discovery.

Functional group (FG) is one of the cornerstone concepts in organic chemistry and related areas. The wide spread of bioisosterism ideas in medicinal chemistry and beyond caused a striking rise in demand for novel FGs with a defined impact on the developed compound properties. In this work, the evaluation of the 3,3-difluorooxetane unit (3,3-diFox) as a functional group for bioisosteric replacements is disclosed. A comprehensive experimental study (including multigram building block synthesis, quantification of steric and electronic properties, measurements of pKa, LogP, chemical stability, and biological evaluation of the 3,3-diFox-derived bioisostere of a drug candidate) revealed a prominent behavior of the 3,3-diFox fragment as a versatile substituent for early drug discovery programs.

Bioisosteric Replacement in the Search for Biologically Active Compounds: Design, Synthesis and Anti-Inflammatory Activity of Novel [1,2,4]triazino[2,3-c]quinazolines.

Background: Designing novel biologically active compounds with anti-inflammatory properties based on condensed quinazolines is a significant area of interest in modern medicinal chemistry. In the present study, we describe the development of promising new bioactive molecules through the bioisosteric replacement of a carbon atom with a sulfur atom in anti-inflammatory agents, specifically 3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)butanoate. Methods: Design and synthetic studies have led to the series of previously unknown substituted 2-[((3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)methyl)thio]carboxylic acids and their esters. These compounds were synthesized by reacting 6-chloroalkyl-3-R-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones with sulfanylalkyl carboxylic acids and their functional derivatives. The purity and structure of the obtained compounds were confirmed using a set of physicochemical methods, including elemental analysis, HPLC-MS, and 1H NMR spectroscopy. Molecular modeling, predicted toxicity, drug-likeness, and pharmacokinetics data were used to select compounds for evaluation of their effects on acute aseptic inflammation (carrageenan-induced paw edema test) and on markers of the inflammatory process. Results: The compound 2-((1-(3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)ethyl)thio)acetic acid (compound 2e) was identified as the most active anti-inflammatory agent (AA = 53.41%), demonstrating significant inhibition of both paw edema development and the generation of pro-inflammatory cytokines and mediators. Conclusions: Results from docking studies and analysis of "structure-affinity" correlations revealed that these compounds are promising candidates for further modification and detailed investigation of their anti-inflammatory activity.

Potent and Protease Resistant Azapeptide Agonists of the GLP‐1 and GIP Receptors

AbstractThe gut‐derived peptide hormones glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) play important physiological roles including glucose homeostasis and appetite suppression. Stabilized agonists of the GLP‐1 receptor (GLP‐1R) and dual agonists of GLP‐1R and GIP receptor (GIPR) for the management of type 2 diabetes and obesity have generated widespread enthusiasm and have become blockbuster drugs. These therapeutics are refractory to the action of dipeptidyl peptidase‐4 (DPP4), that catalyzes rapid removal of the two N‐terminal residues of the native peptides, in turn severely diminishing their activity profiles. Here we report that a single atom change from carbon to nitrogen in the backbone of the entire peptide makes them refractory to DPP4 action while still retaining full potency and efficacy at their respective receptors. This was accomplished by use of aza‐amino acids, that are bioisosteric replacements for α‐amino acids that perturb the structural backbone and local side chain conformations. Molecular dynamics simulations reveal that aza‐amino acid can populate the same conformational space that GLP‐1 adopts when bound to the GLP‐1R. The insertion of an aza‐amino acid at the second position from the N‐terminus in semaglutide and in a dual agonist of GLP‐1R and GIPR further demonstrates its capability as a viable alternative to current DPP4 resistance strategies while offering additional structural variation that may influence downstream signaling.

Polyphenolic Profile and In vitro, In Silico Study of Stem Extracts from J. Maritimus (Juncaceae) Harvested from Eastern Algeria as Potential Anti-Inflammatory and Antioxidant Agents.

Juncus maritimusan extremophilous microorganism speciesknown for its medicinal properties was collected in the Biskra region with the aim of its valorization. The volume size of polyphenols, flavonoids and condensed tannins was performed using the Folin-Ciocalteu method, aluminum trichloride and vanillin respectively. The volume of Polyphenols was 127.73±0.20 μg EAG/mg ES, the volume offlavonoids was 16.42±0.42 μg EQ/mg ES, and the volume ofcondensed tannins was 10.10±0.35 μg EC/mg ES. The results of the antioxidant activity tests using the DPPH and ABTS methods reveal that the ethyl acetate extract had the highest activity in both tests. The results of the in vitro anti-inflammatory activity, using the BSA protein denaturation assay, showed that the percentage of denaturation inhibition wasproportional to the concentration of the extract. At a concentration of 5 mg/mL, the inhibition percentage of the extract were 82.03 % and 80.23 %, respectively,which wereclose tothose of theanti-inflammatory drug Diclofenac.Furthermore, molecular docking simulations indicated that Berberine has high binding affinity to the targets COX-2 and PLA-2 In fact,bioisosteric replacement is being usedto discover new analogs of Berberine. Finally, ADME-Tox predictions demonstrated that this compound and its analogs were not hepatotoxic. This result may lead to the selection ofBerberine and its analogs as active compounds with anti-inflammatory and antioxidant effects.

Synthesis and anti-influenza virus activity of substituted dibenzoxepine-based baloxavir derivatives

Seasonal influenza poses a significant threat to global public health, driving the need for effective anti-influenza agents. The PA protein, which captures the pre-mRNA cap structure, is crucial for the replication of the influenza virus and serves as an important target for developing such agents. Baloxavir, a PA inhibitor, has shown excellent activity against influenza A and B viruses. In this study, its structure was optimized using bioisosteric replacement to develop novel dibenzoxepine-based derivatives for combating influenza. As the lead compounds, ATV03 (EC50 = 0.78 ± 0.10 nM, SI > 64103) and ATV07 (EC50 = 0.78 ± 0.01 nM, SI = 31603) demonstrated excellent anti-influenza A (H3N2) activity and SI, and possessed favorable anti-influenza B activity, with 2.02 ± 0.40 nM and 2.32 ± 0.29 nM of EC50 respectively. They showed improved bioavailability and metabolic stability. Mechanism studies revealed that ATV03 and ATV07 both possessed significant activity in inhibiting PA and RdRp as well as disturbing NP. Consequently, ATV03 was selected for further investigation in the fight against seasonal and pandemic influenza due to its superior bioavailability, metabolic stability, and efficacy against multiple influenza A viruses.

Anti-Schistosomal activity and ADMET properties of 1,2,5-oxadiazinane-containing compound synthesized by visible-light photoredox catalysis.

The incorporation of saturated nitrogen-containing heterocycle 1,2,5-oxadiazinane into small molecules represents a compelling avenue in drug discovery due to its unexplored behavior within biological systems and incomplete protocols for synthesis. In this study, we present 1,2,5-oxadiazinane, an innovative heterocyclic bioisostere of piperizin-2-one and novel chemotype of the anti-schistosomal drug praziquantel (PZQ), which has been the only clinical drug available for three decades. PZQ is associated with significant drawbacks, including poor solubility, a bitter taste, and low metabolic stability. Therefore, the discovery of a new class of anti-schistosomal agents is imperative. To address this challenge, we introduce a pioneering method for the synthesis of 1,2,5-oxadiazinane derivatives through the cycloaddition of nitrones with N,N,N',N'-tetraalkyldiaminomethane in the presence of an IrIII complex photosensitizer. This transformative reaction offers a streamlined route to various kinds of 1,2,5-oxadiazinanes that is characterized by mild reaction conditions and broad substrate scope. Mechanistic investigations suggest that the photoredox pathway underlies the [3 + 3] photocycloaddition process. Thus, based on bioisosteric replacement, we identified a remarkable molecule as a new chemotype of a potent anti-schistosomal compound that not only exhibits superior solubility, but also retains the potent biological activity inherent to PZQ.

Synthesis and antifungal activity of novel piperidinyl thiazole derivatives.

As an investigative program around the development of novel oomycetes fungicides, a systematic exploration of piperidinyl thiazole fungicides employing a bioisosteric replacement strategy was planned. A series of novel piperidinyl thiazole analogues were designed, synthesised, and evaluated as fungicides in vitro and in vivo against three oomycete fungal pathogens: Phytophthora infestans (P. infestans), Plasmopara viticola (P. viticola), and Pseudoperonospora cubensis (P. cubensis). Variation at four different regions of piperidinyl thiazole fungicides like Oxathiapiprolin and Fluoxapiprolin was considered. All variations delivered excellent in vitro and in vivo activity against P. infestans at extremely low concentrations. O-linked heterocyles, bicyclic piperidines, and sulfoximine-substituted aryls demonstrated the most robust transfer of in vitro activity into the greenhouse, while pyridones, acylated sulfoximines, and sultams showed less consistent results concerning the transfer. Specific compounds were selected for deeper evaluation of oomycetes activity. Several of them with representatives of all the series showed an excellent in vivo activity against P. viticola and P. cubensis. Among the most active compounds, P14 and P25 were further profiled in advanced studies and were found to have a robust curative potential. P14, P15, and P25 provided excellent control of P. infestans (in potato), P. viticola (in grapes), and P. cubensis (in cucumber) in field trials at dose rates of 20 and 30 g per hectare. A bioisosteric replacement strategy was successfully employed to identify novel piperidine thiazole derivatives with robust and commercially interesting control of oomycetes diseases in the greenhouse and under field conditions. A systematic exploration of various modifications of the piperidine thiazole class and their structure activity relationships was described. © 2024 Society of Chemical Industry.

Pharmacological Evaluation of Bioisosterically Replaced and TriazoleTethered Derivatives for Anticancer Therapy

Cancer has been the cause of the highest number of deaths in the human population despite the development and advancement in treatment therapies. The toxicity, drug resistance, and side effects of the current medicaments and therapies have left the void for more research and development. One of the possibilities to fill this void is by incorporating Triazole moieties within existing anticancer pharmacophores to develop new hybrid drugs with less toxicity and more potency. The placement of nitrogen in the triazole ring has endowed its characterization of being integrated with anticancer pharmacophores via bioisosteric replacement, click chemistry and organocatalyzed approaches. This review paper emphasizes the discussions from articles published from the early 2000s to the current 2020s about the triazole-based derivatives used in anticancer therapy, elaborating more on their chemical structures, target receptors or enzymes, mechanism of action, structure-activity relationships, different triazole-derived hybrid drugs under clinical and nonclinical trials, and recent advancements toward developing more potent and less toxic anticancer agents.

Discovery of Novel Nicotinamide Derivatives by a Two-Step Strategy of Azo-Incorporating and Bioisosteric Replacement.

Azobenzene moieties can serve as active fragments in antimicrobials and exert trans/cis conversions of molecules. Herein, a series of novel nicotinamide derivatives (NTMs) were developed by employing a two-step strategy, including azo-incorporating and bioisosteric replacement. Azo-incorporation can conveniently provide compounds that can be easily optically interconverted between trans/cis isomers, enhancing the structural diversity of azo compounds. It is noteworthy that the replacement of the azo bond with a 1,2,4-oxadiazole motif through further bioisosteric replacement led to the discovery of a novel compound, NTM18, which made a breakthrough in preventing rice sheath blight disease. A control effect value of 94.44% against Rhizoctonia solani could be observed on NTM18, while only 11.11% was determined for boscalid at 200 mg·L-1. Further mechanism validations were conducted, and the molecular docking analysis demonstrated that compound NTM18 might have a tight binding with SDH via an extra π-π interaction between the oxadiazole ring and residue of D_Y586. This work sets up a typical case for the united applications of azo-incorporating and bioisosteric replacement in fungicide design, posing an innovative approach in structural diversity-based development of pesticides.

Discovery of N-Aryl-N'-[4-(aryloxy)cyclohexyl]squaramide-Based Inhibitors of LXR/SREBP-1c Signaling Pathway Ameliorating Steatotic Liver Disease: Navigating the Role of SIRT6 Activation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily attributed to the abnormal upregulation of hepatic lipogenesis, which is especially caused by the overactivation of the liver X receptor/sterol regulatory element-binding protein-1c (LXR/SREBP-1c) pathway in hepatocytes. In this study, we report the rational design and synthesis of a novel series of squaramides via bioisosteric replacement, which was evaluated for its inhibitory activity on the LXR/SREBP-1c pathway using dual cell-based assays. Compound 31 was found to significantly downregulate LXR, SREBP-1c, and their target genes associated with lipogenesis. Further investigation revealed that compound 31 may indirectly inhibit the LXR/SREBP-1c pathway by activating the upstream regulator sirtuin 6 (SIRT6). Encouragingly, compound 31 substantially attenuated lipid accumulation in HepG2 cells and in the liver of high-fat-diet-fed mice. These findings suggest that compound 31 holds promise as a candidate for the development of treatments for MASLD and other lipid metabolism-related diseases.

Copper-Catalyzed Nucleophilic Cycloisomerization Cascade Constructing Azepinoindolizine.

Numerous effective bioisosteric replacements have been identified through substituting scaffolds and functional groups in lead molecules with alternative ones that preserve or enhance the desired biological activity of the original compound. Here, a copper-catalyzed nucleophilic cycloisomerization was developed to access potential bioisosteric replacements of azepinoindole. In this process, "tetra-alkene" characteristic of indolizine undergoes a 12π electrocyclization, offering a complementary method to obtain azepinoindolizine derivatives that are otherwise challenging to prepare through conventional means.

Bioisosteric replacement of the carboxylic acid group in Hepatitis-C virus NS5B thumb site II inhibitors: phenylalanine derivatives

Hepatitis C virus (HCV) is a global health concern and the NS5B RNA-dependent RNA polymerase (RdRp) of HCV is an attractive target for drug discovery due to its role in viral replication. This study focuses on NS5B thumb site II inhibitors, specifically phenylalanine derivatives, and explores bioisosteric replacement and prodrug strategies to overcome limitations associated with carboxylic acid functionality. The synthesized compounds demonstrated antiviral activity, with compound 6d showing the most potent activity with an EC50 value of 3.717 μM. The hydroxamidine derivatives 7a-d showed EC50 values ranging from 3.9 μM to 11.3 μM. However, the acidic heterocyclic derivatives containing the oxadiazolone (8a-d) and oxadiazolethione (9a-d) rings did not exhibit measurable activity. A methylated heterocycle 10b showed a hint of activity at 8.09 μM. The pivaloyloxymethyl derivatives 11a and 11b did not show antiviral activity. Further studies are warranted to fully understand the effects of these modifications and to explore additional strategies for developing novel therapeutic options for HCV.

Potent and Protease Resistant Azapeptide Agonists of the GLP-1 and GIP Receptors.

The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play important physiological roles. Stabilized agonists of the GLP-1 receptor (GLP-1R) and the GIP receptor (GIPR) for the management of diabetes and obesity have generated widespread enthusiasm and have become blockbuster drugs. These therapeutics are refractory to the action of dipeptidyl peptidase-4 (DPP4), that catalyzes rapid removal of the two N-terminal residues of the native peptides, in turn severely diminishing their activity profiles. Here we report that a single atom change from carbon to nitrogen in the backbone of the entire peptide make them refractory to DPP4 action while still retaining full potency and efficacy at their respective receptors. This was accomplished by use of aza-amino acids, that are bioisosteric replacements for a-amino acids that perturb the structural backbone and local side chain conformations. Molecular dynamics simulations reveal that aza-amino acid can populate the same conformational space that GLP-1 adopts when bound to the GLP-1R. The insertion of an aza-amino acid at the second position from the N-terminus in semaglutide and in a dual agonist of GLP-1R and GIPR further demonstrates its capability as a viable alternative to current DPP4 resistance strategies while offering additional structural variety.

Structure-Activity Relationship of Oxacyclo- and Triazolo-Containing Respiratory Syncytial Virus Polymerase Inhibitors.

Despite the availability of medicines preventing respiratory syncytial virus (RSV) infection, post-exposure treatment options are needed for addressing patient's needs. RSV non-nucleoside polymerase inhibitors (NNI) have emerged as a promising asset for which our group previously disclosed JNJ-8003 with potent in vitro antiviral activity and pronounced in vivo efficacy. In this work, a structural-guided design to modify the linker vector of JNJ-8003 resulted in the identification of 2-oxacyclo pyridine-containing derivatives whose various ring closing strategies are described. In addition, bioisosteric replacement of an amide bond with triazole retained potency, and cryo-electron microscopy (cryo-EM) confirmed binding in the capping domain. Subsequent NMR conformational analysis suggested a correlation between the potency and conformations. Our efforts have fulfilled the aim of identifying linker modifications with maintained biological activity while enriching structural diversity and allowing modulations of other parameters.

Discovery and In Vivo Efficacy of AZ-PRMT5i-1, a Novel PRMT5 Inhibitor with High MTA Cooperativity.

PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel "MTA-cooperative" compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties. Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available in vivo lead compound, 28 ("AZ-PRMT5i-1"), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven in vivo efficacy in several MTAP-deficient preclinical cancer models.

Cu-Electrocatalysis Enables Vicinal Bis(difluoromethylation) of Alkenes: Unraveling Dichotomous Role of Zn(CF2H)2(DMPU)2 as Both Radical and Anion Source.

The difluoromethyl group (CF2H) serves as an essential bioisostere in drug discovery campaigns according to Lipinski's Rule of 5 due to its advantageous combination of lipophilicity and hydrogen bonding ability, thereby improving the ADME properties. However, despite the high prevalence and importance of vicinal hydrogen bond donors in pharmaceutical agents, a general synthetic method for doubly difluoromethylated compounds in the vicinal position is absent. Here we describe a copper-electrocatalyzed strategy that enables the vicinal bis(difluoromethylation) of alkenes. By leveraging electrochemistry to oxidize Zn(CF2H)2(DMPU)2-a conventionally utilized anionic transmetalating source, we paved a way to utilize it as a CF2H radical source to deliver the CF2H group in the terminal position of alkenes. Mechanistic studies revealed that the interception of the resultant secondary radical by a copper catalyst and subsequent reductive elimination is facilitated by invoking the Cu(III) intermediate, enabling the second installation of the CF2H group in the internal position. The utility of this electrocatalytic 1,2-bis(difluoromethylation) strategy has been highlighted through the late-stage bioisosteric replacement of pharmaceutical agents such as sotalol and dipivefrine.