Design, synthesis, and biological evaluation of FXR/ASK1 dual-target modulators

• Xi Zhang,
• Jingyan Wang,
• Ziqiang Zhao,
• Caiyi Wang,
• Zenghui Ye,
• Wei-Yuan Ma,
• Jian-Xing Xu and
• Fengzhi Zhang

Beilstein J. Org. Chem. 2026, 22, 771–781, doi:10.3762/bjoc.22.59

• -aliphatically substituted 4H-1,2,4-triazolopyridine biaryl scaffold of selonsertib [31][39][40], as key pharmacophores. In the co-crystal structure of hFXR-LBD with GW4064 [41], the isoxazole core coordinates the π-cation interaction between His 447 and Trp 469; the 5-isopropyl group is embedded into a

• hydrophobic pocket formed by Phe 284, Leu 287, Trp 454, and Phe 461; the dichlorophenyl moiety engages in π–π stacking with Phe 329; and the meta-positioned carboxy group forms a strong electrostatic interaction with Arg 331. The modification strategies for GW4064 are as follows: The stilbene moiety can be

Synthesis and biological evaluation of new brassinosteroid analogs with C-22 benzoate function

• María Núñez,
• Camila Escobar,
• Mario Párraga,
• Mauricio Soto,
• Luis Espinoza-Catalán,
• Katy Díaz and
• Andrés F. Olea

Beilstein J. Org. Chem. 2026, 22, 753–762, doi:10.3762/bjoc.22.57

• . Keywords: biological activity; brassinosteroids; BRI1-EMS-Suppressor1; ligand–receptor interaction; structure–activity relationship; Introduction Brassinosteroids (BRs) are phytohormones that are widespread in the plant kingdom, and are found in very low concentrations, i.e., in the of nano- to micromolar

• data suggest that the initial step of the signaling process and the subsequent dephosphorylation of BES1 depend on the structure of BRs analogs in the same way. In other words, the interaction between BRs analogs and the binding site determines the response of the plant and one intermediate step

• , conjugation and oxidation via dynamic interaction with different phytohormones and on homeostasis mechanisms [52]. Consequently, exogenous application of a growth regulator initiates not only the process leading to a phenotypic response but also all those associated to its own regulation. Thus, only a

Rongalite addition to dienones: diastereoselectivity in cyclic sulfone synthesis; stereochemical rationalization and prospects as a general conjugate nucleophile

• Melina Goga,
• Hao Zong,
• James Franco,
• Jazmine Prana,
• Rudolph Michel,
• Antonia Muro,
• Elana Rubin,
• Janet Brenya,
• Henk Eshuis and
• Magnus W. P. Bebbington

Beilstein J. Org. Chem. 2026, 22, 742–752, doi:10.3762/bjoc.22.56

• bonds in TS-trans, there is a significant distortion in the chair shape in TS-cis: the two highlighted CH bonds are not parallel – they are converging and this 1,3-diaxial interaction may be a contributing factor in increasing the activation barrier relative to TS-trans. Further technical discussion of

Synthesis of heterocycles based on azomethine ylides from α-amino acids (or amines) and carbonyl compounds

• Ekaterina V. Berezhnaya,
• Alexander I. Ponyaev,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2026, 22, 705–741, doi:10.3762/bjoc.22.55

• , the importance of the formation of azomethine ylides from amino esters, amino acids, imine derivatives, aziridines or other substrates was emphasized. A review [26] demonstrates metal-catalyzed as well as metal-free asymmetric and racemic transformations of imino ethers upon interaction with various

• absence of interaction between the metal and the electron-withdrawing group of the dipolarophile, and the coordination properties of the metal, for example, the possibility of changing the coordination sphere of copper(I) from bidentate to monodentate, which does not occur with the Ag(I) atom, which has

• containing cyclic succinimide, pyrrolidine, pyrrolizidine, and chroman moieties [73] (Scheme 30). The authors showed that the first stage involves intermolecular 1,3-dipolar cycloaddition of azomethine ylides obtained as a result of the interaction of aromatic aldehydes 67 and glycine methyl ester (62) to N

Using generative AI to transform peptide hits into small molecule leads

• Joshua Mills and
• Yu Heng Lau

Beilstein J. Org. Chem. 2026, 22, 672–679, doi:10.3762/bjoc.22.51

• protein–ligand dataset (from Binding MOAD [51]) to factor in the constraints of typical binding pockets. ShEPhERD is an interaction-aware diffusion model developed by Coley and co-workers that is capable of bioisosteric fragment merging [39]. For fragment merging, the model was trained on a subset from

Photoorganocatalytic trifluoromethylation of (het)arenes in green conditions

• Egor N. Boronin,
• Svetlana E. Kaurkina,
• Milena M. Svetlakova,
• Anton S. Bolshakov,
• Maxim V. Arsenyev,
• Vasilii F. Otvagin,
• Alexey Yu. Fedorov,
• Timothy Noël and
• Alexander V. Nyuchev

Beilstein J. Org. Chem. 2026, 22, 662–671, doi:10.3762/bjoc.22.50

• excited state by both TFAA and TMB revealed very similar quenching constants: Kq(TFAA) = 6.07 × 109 M−1·s−1 and Kq(TMB) = 5.37 × 109 M−1·s−1 (Figure S16; for further details, see Supporting Information File 1). These results indicate that either initial interaction is feasible under the reaction

Advantages of PROTACs in achieving selective degradation of homologous protein families

• Luxi Yang,
• Xinfei Mao,
• Jingyi Zhang,
• Jing Shu,
• Wenhai Huang,
• Xiaowu Dong,
• Yinqiao Chen and
• Mingfei Wu

Beilstein J. Org. Chem. 2026, 22, 628–661, doi:10.3762/bjoc.22.49

• ; PROTAC; protein–protein interaction; selectivity; ubiquitination; Introduction The cell is the fundamental unit of structure and function in the human body [1][2]. More than 20,000 proteins act in concert to regulate the entire cellular life process [1]. To date, dysregulated protein function has been

• other non-enzymatic proteins [7] are essentially undruggable using conventional inhibitor-based approaches [4][8]. Consequently, protein–protein interaction (PPI)-based targeted protein degradation (TPD) strategies have attracted increasing attention over the past two decades [9][10]. Among them

• . NanoBRET and ITC experiments indicated that compound 37 induces a stable protein–protein interaction interface between BRD4BD2 and VHL through linker-mediated conformational locking, achieving a cooperativity factor (α) of 117, which is significantly higher than those of compounds 35 and 36. Its co-crystal

Continuous-flow carbonyl hydrogenation under subatmospheric to atmospheric hydrogen pressure enabled by robust heterogeneous Pt–Fe catalysts

• Hiroyuki Miyamura,
• Ryosuke Kajiyama,
• Shun-ya Onozawa,
• Yoshihiro Kon and
• Shū Kobayashi

Beilstein J. Org. Chem. 2026, 22, 575–582, doi:10.3762/bjoc.22.43

• best among the solvents tested (EtOAc, toluene, methylcyclohexane, tetrahydrofuran, and methanol) (see Supporting Information File 1, Figure S5). The hydroxy moiety has a stronger interaction with catalytically active sites at the surface of the heterogeneous catalyst, and smooth desorption of the

Kinetic resolution of racemic planar-chiral vinylcymantrenes by molybdenum-catalyzed asymmetric metathesis dimerization

• Haruna Imazu,
• Hitoshi Izu,
• Yasuhiro Ohki and
• Masamichi Ogasawara

Beilstein J. Org. Chem. 2026, 22, 568–574, doi:10.3762/bjoc.22.42

• in Figure 2) likely inhibits the effective interaction of the substrate with the chiral catalyst, resulting in highly enantioselective kinetic resolution. Cymantrene is far less electron-poor than ferrocene due to the presence of the three carbonyl ligands, which are strong π-acids, on the manganese

Molecular tweezer–peptide conjugates disrupt the protein–protein interaction between survivin and histone H3 essential in mitosis

• Catherine Gsell,
• Philipp Rebmann,
• Karina Opara,
• Christine Beuck,
• Peter Bayer,
• David Bier,
• Ingrid R. Vetter and
• Thomas Schrader

Beilstein J. Org. Chem. 2026, 22, 557–567, doi:10.3762/bjoc.22.41

• , Otto-Hahn-Straße 11, 44227 Dortmund, Germany 10.3762/bjoc.22.41 Abstract Peptide-modified supramolecular tweezers, a promising new class of chemical tools, were designed and employed to inhibit the interaction of the BIR domain of human survivin, a member of the chromosomal passenger complex (CPC

• ; protein–protein interaction; mitosis; X-ray crystallography; Introduction The fundamental process of mitosis is controlled by a very large protein complex called the kinetochore, formed by self-assembly from hundreds of single protein components [1]. For the intricate regulation of the various phases of

• bound tightly to each other by aligning their extended α-helices (Figure 1) [5]. Intriguingly, CPC recruitment hinges on a few very distinct protein contacts, involving borealin and the BIR domain of survivin. A very dominant protein–protein interaction (PPI) is the embedding of the N-terminus of

Experimental and DFT studies on the regioselective methanolysis of 5-azido-9-oxabicyclo[6.1.0]nonan-4-yl 4-nitrobenzoate isomers

• İlknur Polat,
• Selçuk Eşsiz and
• Emine Salamci

Beilstein J. Org. Chem. 2026, 22, 547–556, doi:10.3762/bjoc.22.40

• correlates well with the computed activation barriers and the divergence of the competing reaction pathways. In this context, despite the presence of a hydrogen-bonding interaction in TS2, TS1 is lower in energy due to a more favourable cyclooctane conformation. Notably, the relatively small energy

Melifoliox B, a novel phloroglucin derivative isolated from Melicope barbigera (Rutaceae) and synthesis of new oxidation products from melifoliones A and B

• Horst Weber,
• Kim-Thao Tran-Cong,
• Bernhard Mayer,
• Guido J. Reiss,
• Iryna S. Konovalova,
• Marc S. Appelhans,
• Kenneth R. Wood and
• Claus M. Passreiter

Beilstein J. Org. Chem. 2026, 22, 535–546, doi:10.3762/bjoc.22.39

• , a cross peak was found for the interaction of C-3’ with the protons of the 6-CH3 group. These observations suggest unusual (4J)-long-range C/H-couplings in the rigid spirocyclic 4-ring system. The formation of 11 can be suggested by the following hypothetical pathway (Scheme 3): In a first step, the

Synthesis of a HDAC inhibitor–nanogold probe for cryo-EM visualization in class I HDAC co-repressor complexes

• Wiktoria A. Pytel,
• John W. R. Schwabe and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2026, 22, 480–485, doi:10.3762/bjoc.22.35

• -complete inhibition of the HDAC activity in the CoREST complex, even at 0.54 μM. Surprisingly, Au–NH2 was found to reduce the HDAC activity of the CoREST complex by nearly 50%. One plausible explanation for this effect is a direct interaction between the gold nanoparticles and solvent-accessible cysteine

Synthesis and anti-cancer activity of naphthalimide–organylselanyl conjugates

• Rajkumar Ravi and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2026, 22, 416–435, doi:10.3762/bjoc.22.29

• cancer cell line. Molecular docking simulation revealed strong binding interaction and affinities towards the tyrosine kinase domain of epidermal growth factor receptor (EGFR), and the protein–ligand interaction resembles the interaction found in the co-crystallised protein–erlotinib complex. Result and

• geometry around the selenium atom. The structure reveals the four distinct intermolecular interactions that facilitate the self-assembly in the crystal packing. The first is a chalcogen bonding interaction (Se···Se) [53], as shown in Figure 2b, in which one aryl selenide molecule linearly connects to

• another, with a Se···Se distance of 3.703 Å. The second is a selenium–carbon (Se···C) interaction as shown in Figure 2c, where the molecules are arranged in a top-down orientation [54]. In this orientation, the Se motif of one molecule interacts with the carbonyl carbon of another molecule, showing the Se

Cone p-aminocalix[4]arenes enriched with ‘clickable’ alkyne or azide functionalities

• Ilia Korniltsev,
• Vasily Bazhenov,
• Alexander Gorbunov,
• Dmitry Cheshkov,
• Stanislav Bezzubov,
• Vladimir Kovalev and
• Ivan Vatsouro

Beilstein J. Org. Chem. 2026, 22, 399–415, doi:10.3762/bjoc.22.28

• /receptor units, thus drastically improving their supramolecular interaction capabilities. This property of p-aminocalix[4]arenes has been widely utilized in constructing f-element-targeted extractants for nuclear waste treatment, having four carbamoylmethylphosphine oxide groups introduced to the

Design, synthesis and biological evaluation of 2,5-diaryloxazolo[4,5-d]pyrimidin-7-ylamines as selective cytotoxic agents against HeLa cells

• Maryna V. Kachaeva,
• Agnieszka B. Olejniczak,
• Marta Denel-Bobrowska,
• Victor V. Zhirnov,
• Yevheniia S. Velihina,
• Stepan G. Pilyo and
• Volodymyr S. Brovarets

Beilstein J. Org. Chem. 2026, 22, 390–398, doi:10.3762/bjoc.22.27

• supported by virtual assay results indicating low human toxicity, low probability of interaction with receptors in the Tox21 pathways, very weak substrate specificity for Pgp, very low likelihood of oxidative metabolism, and inability of compound 9 to cross the blood–brain barrier. Hence, according to the

• compounds 1, 7, and 9 determine the threshold values of BBB permeability according to the CNS rule descriptor. Predicted parameters of human toxicity of compounds 1, 7, and 9. Predicted probability of interaction of compound 1, 7, and 9 with nuclear receptor (NR) signaling, and stress response (SR) pathways

Recent advances in the cleavage of non-activated amides

• Eun-Sol Choi and
• Hyo-Jun Lee

Beilstein J. Org. Chem. 2026, 22, 352–369, doi:10.3762/bjoc.22.23

• bromine (Br2), which converts the amide into N-bromobenzamide. Meanwhile, at the cathode, the alcohol is partially deprotonated to form an alkoxide, which engages in a stabilizing hydrogen-bonding interaction to produce the acid–base pair V. Nucleophilic attack of V on N-bromobenzamide forms a tetrahedral

Spirobarbiturates with a pyrrolizidine moiety: synthesis, structure and biological evaluation

• Arthur A. Puzyrkov,
• Andrew S. Drachuk,
• Ekaterina A. Popova,
• Alexander V. Stepakov and
• Vitali M. Boitsov

Beilstein J. Org. Chem. 2026, 22, 274–288, doi:10.3762/bjoc.22.20

• results obtained, docking simulations were performed for the possible interaction of spiro-adducts with actin, as the most widespread and highly conserved cellular protein. Since the initial determination of the G-actin crystal structure in complex with DNase I, many actin structures have been registered

Arene activation via π-bond localization: concepts and opportunities

• Paul Meiners,
• Julian J. Melder and
• Tobias Morack

Beilstein J. Org. Chem. 2026, 22, 257–273, doi:10.3762/bjoc.22.19

• complexes rests on a finely balanced synergistic interaction: the metal center accepts electron density from a filled π orbital of the arene while engaging in π-backbonding, donating electron-density into an empty π* orbital (Figure 4A) [43]. This interaction not only stabilizes the metal–arene bond but

• of the archetypal pentaammineosmium(II) system prior to discussing synthetic utility (Figure 6). The five ammine ligands, strong σ-donors with negligible π-interaction, combined with the d6 configuration render the Os(II) center highly electron-rich and an exceptional π-base [43]. This electronic

•  6B) [45]. Application in organic synthesis Organic transformations of η2-coordinated arenes can be broadly divided into three categories, depending on what dictates reactivity: the polarization of the free molecule, the site of metal coordination, or the backbonding interaction itself. Early studies

Conformational analysis of difluoromethylornithine: factors influencing its gas-phase and bioactive conformations

• Matheus P. Freitas

Beilstein J. Org. Chem. 2026, 22, 237–243, doi:10.3762/bjoc.22.17

• preference arises primarily from hyperconjugative stabilization, particularly the σCH → σ*CN interaction, while steric effects modulate the relative stability among low-energy conformers. The gauche effect is intensified in the zwitterionic form due to electrostatic interactions. In contrast, the

• between natural localized molecular orbitals shows that structure 4 experiences the weakest steric repulsion, whereas structures 1–3 are among the most sterically crowded (Table 1). Several interactions contribute to this trend; notably, the nN/σCC interaction involving the NH₂ group geminal to the

• together with Lewis-type effects control the orientation of the difluoromethyl group, are summarized in Table S1 (Supporting Information File 1). As expected, σCH → σ*CN is the dominant interaction (>3 kcal mol−1) and is present in all type-I structures. When these interactions are summed for each

Configuration–packing synergy enabling integrated crystalline-state RTP and amorphous-state TADF

• Ruiyan Wang and
• Yunan Wu

Beilstein J. Org. Chem. 2026, 22, 224–236, doi:10.3762/bjoc.22.16

• phosphorescence emission was observed for the powder compared to the solution, suggesting that the RTP in the powder phase is influenced by intermolecular packing effects. This observation implies that the organization and interaction between molecules in the solid state play a crucial role in facilitating the

Screwing the helical chirality through terminal peri-functionalization

• Devesh Chandra,
• Sachin and
• Upendra Sharma

Beilstein J. Org. Chem. 2026, 22, 205–212, doi:10.3762/bjoc.22.14

• each other via hydrogen-bonding interaction, locking the relative orientation of the substrates producing the chiral [4]carbohelicene via peri-terminal functionalization (Figure 2). To examine the utility of the developed protocol, the reaction was scaled up to a 2 mmol scale and the product was

• phosphine oxide and the nitro-functionalized oxa[5]helicene. This ion-pairing interaction was also studied using NMR titration and Job’s plot analysis. The transition state depicted in Figure 3 was found to be most favorable providing the product with M-configuration. Looking ahead, these strategies may

Asymmetric Mannich reaction of aromatic imines with malonates in the presence of multifunctional catalysts

• Kadri Kriis,
• Harry Martõnov,
• Annette Miller,
• Mia Peterson,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2026, 22, 151–157, doi:10.3762/bjoc.22.8

• led to the use of multifunctional catalysts of “homocooperativity,” where multiple units of the same catalyst perform different but complementary roles [17]. These catalysts employing noncovalent interactions via hydrogen bonds and also possess Lewis basic and π–π-interaction sites have been highly

• , entry 17), further highlighting the importance of the pyridine ring containing protecting group. The interaction between catalyst E and the imine was further investigated by 19F NMR studies (see Supporting Information File 1). To further elucidate the role of noncovalent interactions, we conducted

• strengthened via hydrogen-bond-assisted halogen bonding [26][30]. Similarly, hydrogen bonds with the amidic proton are also possible. The direct effect of a specific interaction could not be determined based on the obtained data. The network of noncovalent interactions formed stabilizes the complex between the

Symmetrical D–π–A–π–D indanone dyes: a new design for nonlinear optics and cyanide detection

• Ergin Keleş,
• Alberto Barsella,
• Nurgül Seferoğlu,
• Zeynel Seferoğlu and
• Burcu Aydıner

Beilstein J. Org. Chem. 2026, 22, 131–142, doi:10.3762/bjoc.22.6

• theory (DFT) methods. The dyes also exhibit chemosensor properties, showing selectivity for cyanide via a Michael addition mechanism that causes the disappearance of the ICT band, and a significant color change was observed in both organic and aqueous media. In addition, the interaction mechanism between

• under ambient light. In addition, interaction mechanisms of dyes with cyanide were studied using the 1H NMR titration method, and it was determined that they interacted through an addition mechanism. Photophysical properties and interaction mechanisms of the compounds were also supported through density

• groups is disrupted. These results strongly suggest the addition of cyanide to the vinyl bridge. Furthermore, the color of dyes 2a–c, blue, green, and pink, respectively, under ambient light changed to yellow when interacting with cyanide. The interaction mechanism was determined by 1H NMR, and the

Total synthesis of natural products based on hydrogenation of aromatic rings

• Haoxiang Wu and
• Xiangbing Qi

Beilstein J. Org. Chem. 2026, 22, 88–122, doi:10.3762/bjoc.22.4

• substrate electronic environments [29]. Reactivity is governed by the electron density of arenes, which directly influences kinetics and product distributions [30][31]. The inability to generically modulate this interaction has confined most catalytic systems to narrow substrate scopes. Addressing this