Synthetic study toward vibralactone

• Liang Shi,
• Jiayi Song,
• Yiqing Li,
• Jia-Chen Li,
• Shuqi Li,
• Li Ren,
• Zhi-Yun Liu and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2025, 21, 2376–2382, doi:10.3762/bjoc.21.182

• vibralactone, a potent inhibitor of pancreatic lipase, is reported. The synthesis of the challenging all-carbon quaternary center within the cyclopentene ring was achieved through intramolecular alkylidene carbene C–H insertion. Keywords: alkylidene carbene; C–H insertion; total synthesis; vibralactone

• moiety have been isolated and demonstrate potent bioactivities [7] (Figure 1). For example, lactacystin (1) which was isolated by Ōmura and co-workers [8][9], is a potent and selective proteasome inhibitor; its active form is the synthetic precursor omuralide (2) [10][11]. Similarly, salinosporamide (3

• ), a marine natural product isolated by Fenical and co-workers [12], also acts as a proteasome inhibitor and displays more potent in vitro cytotoxicity than omuralide (2). Anisatin (4), which contains a characteristic spiro β-lactone has been identified as a noncompetitive antagonist of GABA-gated ion

Recent advances in Norrish–Yang cyclization and dicarbonyl photoredox reactions for natural product synthesis

• Peng-Xi Luo,
• Jin-Xuan Yang,
• Shao-Min Fu and
• Bo Liu

Beilstein J. Org. Chem. 2025, 21, 2315–2333, doi:10.3762/bjoc.21.177

• inhibitor [53][54]. In 2018, Suzuki’s group employed their developed photoredox reaction to carry out a model study on the chiral [5,6]-spiroketal core of γ-rubromycin [50]. 1,2-Naphthoquinone 106 was selected as the model substrate for the photoredox reaction (Scheme 13a). Lawsone (101) underwent reductive

Halogenated butyrolactones from the biomass-derived synthon levoglucosenone

• Johannes Puschnig,
• Martyn Jevric and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2025, 21, 2297–2301, doi:10.3762/bjoc.21.175

• reduced form 6, which is sold as a solvent, is an inexpensive commercially available reagent (Scheme 1) [21]. Monohalogenation of LGO giving chloride 7a [22] and bromide 7b [23] is readily achieved in a single step, however, fluorinated 7c, which is a potent inflammasone inhibitor (0.8 ± 0.5 µM), has only

Research towards selective inhibition of the CLK3 kinase

• Vinay Kumar Singh,
• Frédéric Justaud,
• Dabbugoddu Brahmaiah,
• Nangunoori Sampath Kumar,
• Blandine Baratte,
• Thomas Robert,
• Stéphane Bach,
• Chada Raji Reddy,
• Nicolas Levoin and
• René L. Grée

Beilstein J. Org. Chem. 2025, 21, 2250–2259, doi:10.3762/bjoc.21.172

• , Khudwadhar, Gulaothi, Bulandshahr, Uttar Pradesh-203408, India Chemveda Life Sciences India Pvt. Ltd., B-11/1, IDA Uppal, Hyderabad-500039, Telangana, India Sorbonne Université, CNRS, FR 2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening facility), Station Biologique de Roscoff, CS

• splicing process. Among the four isoforms of CLKs, CLK3 is the one for which the biological roles are less understood, in part because no selective inhibitor of this challenging kinase has been found to date. Based on structural analysis of the CLKs we have identified the lysine 241, present only in CLK3

• VS-77 which has now a significant affinity toward CLK3 (IC50 = 0.3 μM). Thus, VS-77 appears as a new pan-inhibitor of the CLK family. Keywords: cancer; CLK3; kinases; molecular modelling; quinazolines; triazoles; Introduction Human protein kinases are a family comprising nearly 535

Electrochemical cyclization of alkynes to construct five-membered nitrogen-heterocyclic rings

• Lifen Peng,
• Ting Wang,
• Zhiwen Yuan,
• Bin Li,
• Zilong Tang,
• Xirong Liu,
• Hui Li,
• Guofang Jiang,
• Chunling Zeng,
• Henry N. C. Wong and
• Xiao-Shui Peng

Beilstein J. Org. Chem. 2025, 21, 2173–2201, doi:10.3762/bjoc.21.166

• used as an inhibitor of cyclin dependent kinase (CDK8) [31]. Sulfonamide-N-benzoxaborole analog GSK8175 is an inhibitor against hepatitis C virus (HCV) [20] (Figure 1). The construction of five-membered rings obtained growing attention [32][33][34][35][36][37][38], and alkynes [39][40][41][42][43][44

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

Research progress on calixarene/pillararene-based controlled drug release systems

• Liu-Huan Yi,
• Jian Qin,
• Si-Ran Lu,
• Liu-Pan Yang,
• Li-Li Wang and
• Huan Yao

Beilstein J. Org. Chem. 2025, 21, 1757–1785, doi:10.3762/bjoc.21.139

• and enhanced the overall solubility and biocompatibility of the azo-calixarene structure, designing it as a drug carrier (Figure 18) [126]. This carrier binds to the ferroptosis inhibitor liproxstatin-1 (Lip) and releases it selectively in hypoxic environments. This mechanism aims to counteract the

Approaches to stereoselective 1,1'-glycosylation

• Daniele Zucchetta and
• Alla Zamyatina

Beilstein J. Org. Chem. 2025, 21, 1700–1718, doi:10.3762/bjoc.21.133

• , respectively [64]. The use of TMS-stabilized lactol acceptors also found application in the synthesis of an E-selectin inhibitor. The tribenzylated TMS-β-galactose acceptor 56 was reacted with the tetrabenzylated mannosyl fluoride donor 55, ensuring high stereoselectivity in the formation of the α,β-1,1

• '-conjugated product 57, a precursor of the E-selectin inhibitor (Scheme 5) [39][40]. However, when the benzyl protecting groups were replaced with acetyl groups, as in the case of the tetraacetylated Gal-derived acceptor 58, the anomeric hydroxy group could only be partially trapped in the β-configuration (α

Highly distinguishable isomeric states of a tripodal arylazopyrazole derivative on graphite through electron/hole-induced switching at ambient conditions

• Himani Malik,
• Sudha Devi,
• Debapriya Gupta,
• Ankit Kumar Gaur,
• Sugumar Venkataramani and
• Thiruvancheril G. Gopakumar

Beilstein J. Org. Chem. 2025, 21, 1496–1507, doi:10.3762/bjoc.21.112

• imparted quantitative and reversible photoswitching [20][21]. The long-term photoswitching stability and tunable half-lifes of Z isomers of azopyrazole-based switches [20][21][22] have made their way to several applications in thermal energy storage [23], photoswitchable inhibitor [24], photoswitchable

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• intramolecular E2 elimination. Finally, the importance and power of the intramolecular Williamson etherification has also been demonstrated by the kilogram-scale synthesis of oxetane intermediate 41, which is a key intermediate in the preparation of the previously mentioned IDO1 inhibitor 2 (Scheme 9) [16

Recent advances in oxidative radical difunctionalization of N-arylacrylamides enabled by carbon radical reagents

• Jiangfei Chen,
• Yi-Lin Qu,
• Ming Yuan,
• Xiang-Mei Wu,
• Heng-Pei Jiang,
• Ying Fu and
• Shengrong Guo

Beilstein J. Org. Chem. 2025, 21, 1207–1271, doi:10.3762/bjoc.21.98

A multicomponent reaction-initiated synthesis of imidazopyridine-fused isoquinolinones

• Ashutosh Nath,
• John Mark Awad and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 1161–1169, doi:10.3762/bjoc.21.92

• reaction followed by the cleavage of the alkyl group to give intermediate II as a free amine. Annulation of II with CDI gave product B which is an HIV reverse transcriptase inhibitor (Scheme 1B) [17]. We have reported a three-component [3 + 2] cycloaddition followed by IMDA reaction for making heterocyclic

Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold

• Henry S. T. Smith,
• Ben Giuliani,
• Kanchana Wijesekera,
• Kah Yean Lum,
• Sandra Duffy,
• Aaron Lock,
• Jonathan M. White,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2025, 21, 1126–1134, doi:10.3762/bjoc.21.90

• ]pyrazine (hereafter referred to as “triazolopyrazine”) analogues, including derivatives inherited from Pfizer and newly synthesised analogues [5]. Triazolopyrazine compounds of OSM series 4 are believed to dysregulate P. falciparum ATP4ase (PfATP4), possibly as a direct inhibitor [5]. Series 4 compounds

Synthesis of pyrrolo[3,2-d]pyrimidine-2,4(3H)-diones by domino C–N coupling/hydroamination reactions

• Ruben Manuel Figueira de Abreu,
• Robin Tiedemann,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2025, 21, 1010–1017, doi:10.3762/bjoc.21.82

• leukaemia, and TAK-285 (H) is a promising HER2/EGFR inhibitor which has been tested in a phase 1 trial on humans as an anticancer agent (Figure 1) [16]. Given the significance of deazapurines as biologically active lead compounds [22], we developed a new methodology for the synthesis of uracil-based

• activities. Development of drugs based on pyrrolopyrimidines: A: Cadeguomycin. B: Tubercidin. C: Toyocamycin. D: Batzelladine A. E: Sangivamycin. F: Pemetrexed. G: Immucillin H. H: TAK-285 (tyrosine kinase inhibitor). UV–vis absorption (left) and emission (right, λex = 300 nm) spectra of compounds 4a, 4j, 4k

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• , outperforming other compounds in the group, such as 5a (IC50 = 78.65 ± 6.88 µM) and 5b (IC50 = 95.66 ± 9.93 µM). These findings suggest that pyrrolidine-2,3-dione derivative 5e holds significant potential as an effective iNOS inhibitor. Conclusion In this study, a series of 4-(1-methylamino)ethylidene-1,5

Orthogonal photoswitching of heterobivalent azobenzene glycoclusters: the effect of glycoligand orientation in bacterial adhesion

• Leon M. Friedrich and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2025, 21, 736–748, doi:10.3762/bjoc.21.57

• relationships between ligand orientation and anti-adhesive properties of the respective inhibitor. Biological testing For the adhesion-inhibition assays, type-1-fimbriated E. coli bacteria were employed where the α-ᴅ-mannoside-specific adhesion is mediated by the fimbrial lectin FimH. According to a known

• adhesion in serial dilutions leading to dose–response inhibition curves from which IC50 values for each inhibitor were deduced (cf. Supporting Information File 1, Figures S13–S16). As these values can vary between individual assays quite significantly, IC50 values for each inhibitor are compared to methyl

• orthogonally photoswitchable glycocluster combining an azobenzene α-ᴅ-mannoside and an azobenzene β-ᴅ-glucoside unit on a methyl mannoside scaffold (1) [24]. In this account, the heterobivalent glycocluster 1 was tested as inhibitor of mannose-specific bacterial adhesion in its various isomeric states (EE, EZ

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• pendant aryl moiety, is better for target-binding and hence 41 is a ≈10-fold more potent inhibitor of BACE-1 than 40. Several further examples of cyclic ethers will be examined in section 5 (sugars). The anomeric effect applies in acyclic ethers, too. Consider the non-fluorinated scaffold, Ph–O–CH3 (42

• orthogonal in 47 [84], leading to different overall molecular shapes for compounds 46 and 47. Another illustration of this phenomenon is seen with the macrocycles 48 and 49, which are simplified analogues of a known BACE-1 inhibitor [85]. In the non-fluorinated macrocycle 48, the aryl ether moiety features a

• enzyme, and the hydroxy group of 57 interacts with catalytic aspartate residues in the active site. The fluorinated pepstatin analogue 58 was predicted to be pre-organised into the bent conformation and hence be a more potent inhibitor than 57. Compound 58 was indeed found to be more potent than 57

Entry to 2-aminoprolines via electrochemical decarboxylative amidation of N‑acetylamino malonic acid monoesters

• Olesja Koleda,
• Janis Sadauskis,
• Darja Antonenko,
• Edvards Janis Treijs,
• Raivis Davis Steberis and
• Edgars Suna

Beilstein J. Org. Chem. 2025, 21, 630–638, doi:10.3762/bjoc.21.50

• cyclic amino acids are common structural motifs in the design of small-molecule drugs and peptidomimetics [1]. For example, the clinically used anesthetics carfentanil (1) and remifentanil (2), the FDA-approved antipruritic medication defelikefalin (3), and the arginase inhibitor 4 [2] possess cyclic α,α

• -disubstituted piperidine-containing amino acid subunits. Likewise, a cyano-substituted cyclic aminal is a core structural unit of the fibroblast activation protein inhibitor 5 [3] (Figure 1). The widespread use of non-proteinogenic cyclic amino acids in drug discovery justifies both the design of new analogs

Synthesis of N-acetyl diazocine derivatives via cross-coupling reaction

• Thomas Brandt,
• Pascal Lentes,
• Jeremy Rudtke,
• Michael Hösgen,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2025, 21, 490–499, doi:10.3762/bjoc.21.36

• designing a photoswitchable drug is to place the switch at a position in the pharmacophore that allows switching of the biological effect by irradiation with light without greatly reducing the overall activity by unselective interference with the inhibitor–receptor interaction. This is a difficult task

• efficiency. In any case the light-induced geometry change via isomerization should selectively control the interaction between the inhibitor and the receptor [21]. Currently there is only one example reported in the literature for the incorporation of N-acetyl diazocines into biologically active molecules

• switching properties even in an aqueous environment and are therefore promising switches in photopharmacological applications. a) Structural similarity of N-acetyl diazocine 1 with known 17βHSD3-inhibitor tetrahydrodibenzazocine (THB) [17] and parent diazocine with steroid scaffolds [18]. b) Parent

Organocatalytic kinetic resolution of 1,5-dicarbonyl compounds through a retro-Michael reaction

• James Guevara-Pulido,
• Fernando González-Pérez,
• José M. Andrés and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2025, 21, 473–482, doi:10.3762/bjoc.21.34

• yields [27]. These reactions have been utilized in the enantioselective synthesis of aryl sulfoxides through the arylation of sulfonate anions in the presence of palladium catalysts [28][29]. They have also been used in the synthesis of the neuraminidase inhibitor (−)-oseltamivir [30] and the

Synthesis, characterization, antimicrobial, cytotoxic and carbonic anhydrase inhibition activities of multifunctional pyrazolo-1,2-benzothiazine acetamides

• Ayesha Saeed,
• Shahana Ehsan,
• Muhammad Zia-ur-Rehman,
• Erin M. Marshall,
• Sandra Loesgen,
• Abdus Saleem,
• Simone Giovannuzzi and
• Claudiu T. Supuran

Beilstein J. Org. Chem. 2025, 21, 348–357, doi:10.3762/bjoc.21.25

• complex as the amide coupling agent with thionyl chloride [38] (Figure 1C). Recently, benzothiazine scaffolds of phenyl acetamides were synthesized as potent inhibitors for ureolytic infections [39] (Figure 1D). Saccharine (a sweetener) was reported to be a potent carbonic anhydrase inhibitor (CAI) by

Visible-light-promoted radical cyclisation of unactivated alkenes in benzimidazoles: synthesis of difluoromethyl- and aryldifluoromethyl-substituted polycyclic imidazoles

• Yujun Pang,
• Jinglan Yan,
• Nawaf Al-Maharik,
• Qian Zhang,
• Zeguo Fang and
• Dong Li

Beilstein J. Org. Chem. 2025, 21, 234–241, doi:10.3762/bjoc.21.15

• properties that can modify the activity and pharmacokinetic profiles of drugs [7]. Prominent examples include pantoprazole, a widely used proton-pump inhibitor (PPI) featuring a CF2H group; deracoxib, another drug that also incorporates a CF2H moiety in its structure; and a MET inhibitor specifically

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• concentrations in the later stages of this pathology, has been gaining attention for the treatment of this disease. In 2021, Brandão et al. [33] developed a series of molecules inspired by the oxoindole-β-lactam core, a structural motif, present in many acetylcholinesterase inhibitor drugs, through the Ugi

• showed more potency than galantamine (IC50 = 3.9 μM), a cholinesterase inhibitor in clinical use against AD. In the search for novel ligands for Alzheimer's treatment, a common strategy involves the combination of structural fragments from different molecules. This concept often yields new compounds with

• new family of ferulic acid–tacrine hybrids (FATHs), using the Ugi reaction. FATHs were selected because tacrine is a well-known cholinesterase (ChE) inhibitor, although it is hepatotoxic, and ferulic acid is a potent antioxidant. Fourteen FATH were synthesized and tested for hepatotoxicity

Synthesis of the 1,5-disubstituted tetrazole-methanesulfonylindole hybrid system via high-order multicomponent reaction

• Cesia M. Aguilar-Morales,
• América A. Frías-López,
• Nadia V. Emilio-Velázquez,
• Alejandro Islas-Jácome,
• Angelica Judith Granados-López,
• Jorge Gustavo Araujo-Huitrado,
• Yamilé López-Hernández,
• Hiram Hernández-López,
• Luis Chacón-García,
• Jesús Adrián López and
• Carlos J. Cortés-García

Beilstein J. Org. Chem. 2024, 20, 3077–3084, doi:10.3762/bjoc.20.256

• representative studies include antibacterial, anti-inflammatory, antioxidant, selective inhibitor of COX-2 [34], and anti-HIV activity [35]. In this context, even though indole is considered a privileged scaffold present in some anticancer agents [36], a few examples of methanesulfonylindoles are studied as

N-Glycosides of indigo, indirubin, and isoindigo: blue, red, and yellow sugars and their cancerostatic activity

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2840–2869, doi:10.3762/bjoc.20.240

• mentioned above, that the free NH function of indirubin is important for CDK inhibition. We have shown in our group by enzyme studies that glycoside β-33b, lacking the free NH-function, does not act as a CDK inhibitor, despite its high activity against melanoma cells and other cancers [32]. These results

• carbohydrate moiety is later hydrolytically cleaved in the cell to release the indirubin which then acts as a CDK inhibitor. A synergistic effect of plasma-activated medium (PAM) and β-33b on human skin cancer cells was observed [32][33]. With regard to viability, adhesion capacity, apoptosis and G2/M cell

• STAT3 (signal transducer and activator of transcription 3) were observed as biochemical pathways, along with downregulation of antiapoptotic XIAP (X-linked inhibitor of apoptosis protein) and surviving as well as upregulation of the proapoptotic Bcl-2 protein Puma and the cell cycle inhibitor p21. It is