Thiazolidinones: novel insights from microwave synthesis, computational studies, and potentially bioactive hybrids

• Luan A. Martinho,
• Victor H. J. G. Praciano,
• Guilherme D. R. Matos,
• Claudia C. Gatto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2025, 21, 2618–2636, doi:10.3762/bjoc.21.203

• ]. Some rhodanine-based derivatives act as inhibitors of hepatitis C virus (HCV) protease [19], UDP-N-acetylmuramate/ʟ-alanine ligase [20], histidine decarboxylase [21], aldose/aldehyde reductase [22], fungal protein mannosyl transferase 1 (PMT1) [23], metallo β-lactamase [24], cathepsin D [25], JNK

Synthesis and characterization of a isothiouronium-calix[4]arene derivative: self-assembly and anticancer activity

• Giuseppe Granata,
• Loredana Ferreri,
• Claudia Giovanna Leotta,
• Giovanni Mario Pitari and
• Grazia Maria Letizia Consoli

Beilstein J. Org. Chem. 2025, 21, 2535–2541, doi:10.3762/bjoc.21.195

• class of interest in the search for new chemotherapeutic agents. They are known inhibitors of protein kinase C [40] and agonists of the GABA-type [41] and histamine-H3 receptors [42]. S-Allylic isothiouronium salts substituted with aliphatic groups have shown to combine high antitumor activity against

Effect of a photoswitchable rotaxane on membrane permeabilization across lipid compositions

• Udyogi N. K. Conthagamage,
• Lilia Lopez,
• Zuliah A. Abdulsalam and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2498–2512, doi:10.3762/bjoc.21.192

• bacteria or malignant cells like cancer) [5][6], or to influence membrane protein function and thereby control cellular behavior [7][8]. One promising approach is the development of light-activated molecules that can modulate membrane properties upon irradiation, enabling remote activation with high

Assembly strategy for thieno[3,2-b]thiophenes via a disulfide intermediate derived from 3-nitrothiophene-2,5-dicarboxylate

• Roman A. Irgashev

Beilstein J. Org. Chem. 2025, 21, 2489–2497, doi:10.3762/bjoc.21.191

• developed for photothermal and photodynamic therapy, where their π-conjugated frameworks contribute to both imaging and therapeutic functions [19]. Some other TT-based compounds have been reported to inhibit specific carbonic anhydrase isoforms [20], protein tyrosine phosphatase 1B [21], as well as to act

Comparative analysis of complanadine A total syntheses

• Reem Al-Ahmad and
• Mingji Dai

Beilstein J. Org. Chem. 2025, 21, 2334–2344, doi:10.3762/bjoc.21.178

• glial cells, rendering complanadine A a promising lead compound for neurological disorder treatment. Later, complanadine A was also identified as a lead compound for pain management by Siegel and co-workers [8]. They discovered one of its potential cellular targets as the Mas-related G protein-coupled

Enantioselective radical chemistry: a bright future ahead

• Anna C. Renner,
• Sagar S. Thorat,
• Hariharaputhiran Subramanian and
• Mukund P. Sibi

Beilstein J. Org. Chem. 2025, 21, 2283–2296, doi:10.3762/bjoc.21.174

• selective synthesis owing to their unprecedented catalytic activity and selectivity. Advances in the field of protein engineering have made enzymatic catalysis more amenable to enantioselective organic synthesis in the past decade. Recent advances in the development of synergistic catalytic systems

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

• 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

• phosphotransferases (called the human kinome) involved in specific signaling pathways which regulate cell functions (e.g., metabolism, cell cycle progression, cell adhesion, vascular function, and angiogenesis). Therefore, the dysregulation of protein kinase enzymatic activity, induced by genetic alterations as well

• as overexpression, is implicated in the pathogenesis of numerous deleterious diseases including nervous and inflammatory disorders as well as a number of malignancies [1][2][3]. Kinases are also known to be highly druggable by both allosteric and competitive inhibitors. As a consequence, protein

Thiadiazino-indole, thiadiazino-carbazole and benzothiadiazino-carbazole dioxides: synthesis, physicochemical and early ADME characterization of representatives of new tri-, tetra- and pentacyclic ring systems and their intermediates

• Gyöngyvér Pusztai,
• László Poszávácz,
• Anna Vincze,
• András Marton,
• Ahmed Qasim Abdulhussein,
• Judit Halász,
• András Dancsó,
• Gyula Simig,
• György Tibor Balogh and
• Balázs Volk

Beilstein J. Org. Chem. 2025, 21, 2220–2233, doi:10.3762/bjoc.21.169

• microsome (HLM) fractions were thawed on ice and diluted in 0.05 M potassium phosphate buffer (pH 7.4) to a final protein concentration of 1.25 mg/mL. Test compounds were dissolved in DMSO to create stock solutions of 5 mM. The drug concentration in the final assays was 10 μM. The assay was performed in

• conditions using Equation 5: where the HLM protein per gram of liver was equal to 25 and the liver weight per standard body was equal to 49. Testosterone was included as a positive control to confirm metabolic competence of the HLM fractions, with and without cofactors. Zero-time samples served as 100

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

• F and cryptotrione have fused and spiro five-membered rings, respectively [25][26]. Strepsesquitriol bearing bridged five-membered rings was firstly synthesized by Li in 2024 [27]. The green fluorescent protein (GFP) core chromophore (o-LHBDI) displayed a potential application in organic light

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

• temperatures between 180–240 ºC in a maximum yield of about 30–40% (Scheme 14) [72][73]. Dihydroxyacetone (DHA) The formose process is the conversion of formaldehyde to glycolaldehyde and 1,3-dihydroxy-2-propanone (dihydroxyacetone, DHA). A computational protein-directed evolution allowed to create "formolase

Rhodium-catalysed connective synthesis of diverse reactive probes bearing S(VI) electrophilic warheads

• Scott Rice,
• Julian Chesti,
• William R. T. Mosedale,
• Megan H. Wright,
• Stephen P. Marsden,
• Terry K. Smith and
• Adam Nelson

Beilstein J. Org. Chem. 2025, 21, 1924–1931, doi:10.3762/bjoc.21.150

• the discovery of small molecule modifiers for investigating and engineering proteins. Keywords: covalent probes; molecular diversity; rhodium carbenoids; Introduction Diverse sets of reactive probes can facilitate the discovery of chemical tools and drugs that chemically modify protein targets [1][2

Synthesis, biological and electrochemical evaluation of glycidyl esters of phosphorus acids as potential anticancer drugs

• Almaz A. Zagidullin,
• Emil R. Bulatov,
• Mikhail N. Khrizanforov,
• Damir R. Davletshin,
• Elvina M. Gilyazova,
• Ivan A. Strelkov and
• Vasily A. Miluykov

Beilstein J. Org. Chem. 2025, 21, 1909–1916, doi:10.3762/bjoc.21.148

• interactions. The method provides insight into protein structures and functions using electrochemical methods that can also be applied to studies involving alkylating agents [25][26]. In this study, LSV was employed to investigate the interactions between human serum albumin (HSA) and the three prospective

• albumin was chosen as a model protein because of its well‐characterized structure and the presence of reactive sites that are known to be susceptible to alkylation. In standard aqueous media, the electrochemical oxidation of HSA can be observed via LSV as a broad wave, which is often attributed to the

• oxidation of amide and other amino acid side‐chain fragments. By tracking changes in this oxidation signal upon addition of an alkylating agent, we can infer whether the agent has effectively reacted with (and thus structurally altered) the protein. As illustrated by the black trace in the LSV plot, pure

Photoswitches beyond azobenzene: a beginner’s guide

• Michela Marcon,
• Christoph Haag and
• Burkhard König

Beilstein J. Org. Chem. 2025, 21, 1808–1853, doi:10.3762/bjoc.21.143

• the protein-binding site than the bent Z-isomer. However, it would be more desirable to have an inactive molecule in its most stable state which can be activated by irradiation [51][59]. Hernando and co-workers were able to design photoswitchable neurotransmitters of ionotropic kainate receptors by

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

• and protein which enhance the stability of the complex [37][38]. The molecular docking study evaluated the binding affinities of potential drug candidates (iNOS–5a, 5b, 5c, 5d, 5e) and the reference compound (iNOS–DEX) with the inducible nitric oxide synthase (iNOS) enzyme (Figure 4 and Figure 5). The

• , Trp194, Gly202, Pro350, Phe369, and Tyr489, further contributing to the stabilization of the ligand–protein complexes. More importantly, the occurrence of an electron-withdrawing group, nitro group (NO2), on the aromatic ring linked to the 1-position of the pyrrolidine-2,3-dione core may help compound 5e

• stabilized the ligand–protein complexes. Experimental evaluations have confirmed these findings in which compound 5e demonstrated the most potent inhibitory activity against iNOS, achieving an IC50 value of 43.69 ± 5.26 µM substantially lower than that of 5a (IC50 = 78.65 ± 6.88 µM) and 5b (IC50 = 95.66

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

• the structural determinants of the recognition process is a prerequisite for understanding and manipulating carbohydrate–protein interactions, such as in the inhibition of carbohydrate-specific bacterial adhesion. For receptor binding, glycoligands have to be properly oriented in three-dimensional

• ; Introduction Carbohydrate–protein interactions are fundamental in cell biology, such as in cell–cell interactions, immune cell trafficking or bacterial adhesion, and therefore carbohydrate recognition is subject of intensive research. In particular, a plethora of synthetic glycoconjugates have been designed

• diverse interactions with primary and secondary carbohydrate binding sites of the protein [13]. For example, when an α-ᴅ-mannopyranosyl (Man) and a β-ᴅ-glucopyranosyl (Glc) unit were conjugated such that the relative orientation of the two sugar portions is varied – be it on enantiomeric or regioisomeric

Synthesis of HBC fluorophores with an electrophilic handle for covalent attachment to Pepper RNA

• Raphael Bereiter and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 727–735, doi:10.3762/bjoc.21.56

• fluorescent protein (GFP), has revolutionized genetics by providing highly accurate real-time detection of fusion proteins in vitro and in vivo [1]. Pioneering work on GFP-tagged proteins for real-time monitoring of gene expression was first reported by Chalfie and co-workers in 1994 [2]. For a long time

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

• *C1–O5 hyperconjugation. Therefore, if the anomeric oxygen is replaced with CH2 (e.g., 78, Figure 10), the anomeric bonds are able to rotate more freely, and this manifests in a reduced binding affinity for the protein target by 78 compared to 77. However, upon progressing to a CHF linkage (e.g., 79

• and 80, Figure 10), the molecule becomes more rigid again, this time due to dual σC–H → σ*C–F hyperconjugation. Notably, different conformations are preferred by the epimeric fluorinated analogues 79 and 80: analogue 79 is a good match for the parent disaccharide and retains its protein-binding

• which the conformation can be controlled by fluorine, is the natural product balanol (99, Figure 11) [112][167][168][169][170][171][172]. Balanol is an ATP mimic that inhibits protein kinase Cε (PKCε), an enzyme that is implicated in cancer. However, compound 99 also inhibits off-target kinases

Asymmetric synthesis of fluorinated derivatives of aromatic and γ-branched amino acids via a chiral Ni(II) complex

• Maurizio Iannuzzi,
• Thomas Hohmann,
• Michael Dyrks,
• Kilian Haoues,
• Katarzyna Salamon-Krokosz and
• Beate Koksch

Beilstein J. Org. Chem. 2025, 21, 659–669, doi:10.3762/bjoc.21.52

• spheres of protein engineering and medicinal chemistry. In the last decades, a large number of different synthetic strategies have been developed to produce a large variety of fluorinated amino acids. Still, obtaining fluorinated amino acids in great quantities can be challenging, or the corresponding

• amino acids. We synthesized two fluorinated analogs of phenylalanine, which are still unexplored in the context of peptide and protein chemistry. Furthermore, both diastereomers of trifluoroleucine were synthesized, demonstrating that the described strategy can also be applied to synthesize enantio‑ and

• -natural amino acids are pivotal in protein engineering and drug development. Over 30% of approved small‑molecule drugs today contain non‑canonical amino acid building blocks [1][2]. In peptide and protein engineering, non‑natural amino acids significantly increase the respective range of tools used to

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

• -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

Photocatalyzed elaboration of antibody-based bioconjugates

• Marine Le Stum,
• Eugénie Romero and
• Gary A. Molander

Beilstein J. Org. Chem. 2025, 21, 616–629, doi:10.3762/bjoc.21.49

• decision-making [6][7]. Antibody–oligonucleotide conjugates, antibody–enzyme conjugates, antibody–polymer conjugates, antibody–nanomaterial conjugates, antibody–catalyst conjugates, and antibodies involved in protein degradation also play critical roles in biomedical research and therapies [2]. In whatever

• additionally generate an undesirable new stereocenter [26][27]. Few methods have been developed for the functionalization of tyrosine (Tyr) and tryptophan (Trp). With a low abundance (≈3%) in proteins, Tyr modifications are widely recognized for their ability to profoundly impact protein properties and

• different molecules, such as a drug and a targeting moiety. This technique has been shown to be useful in applications such as cell labeling, protein–protein interactions, and photoradiosynthesis of bioconjugates, but the most important challenge remains the lack of specificity to target one amino acid, and

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

• accumulation in the environment after excretion [1][6][7]. These superior properties of diazocines have been exploited in several applications such as the control of protein folding by implementation as cross-linkers between protein side chains [8] or in peptide backbones [9], as photoswitchable

Synthesis of electrophile-tethered preQ₁ analogs for covalent attachment to preQ₁ RNA

• Laurin Flemmich and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 483–489, doi:10.3762/bjoc.21.35

• transcription or translation of the mRNA and results in altered transcript and/or protein levels [5]. In recent years, there has been a growing interest in the modification of preQ1. preQ1 derivatives, preQ1 analogs and mimics of preQ1 have greatly expanded our understanding of preQ1-binding biomolecules, such

• preQ1 congeners into oligonucleotide strands at specific recognition sites. In addition, the potential of modified preQ1 for protein enzyme-independent RNA labeling has also been demonstrated [12][17]. In a recent study [4], sequence-specific RNA–small molecule crosslinking (Scheme 1B) was achieved in

• our research program to tailor non-covalent RNA–small molecule ligands to their covalent counterparts. While “covalent drugs” have become a leading principle in medicinal chemistry in the “protein world” [35][36] – approximately 30% of all FDA-approved drugs form a covalent bond with their target

Identification and removal of a cryptic impurity in pomalidomide-PEG based PROTAC

• Bingnan Wang,
• Yong Lu and
• Chuo Chen

Beilstein J. Org. Chem. 2025, 21, 407–411, doi:10.3762/bjoc.21.28

• Bingnan Wang Yong Lu Chuo Chen Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA 10.3762/bjoc.21.28 Abstract Chemically induced dimerization is a powerful tool for studying protein function, wherein the IMiD (the “immunomodulatory

• drug”) class of PROTAC molecules with a PEG linker is frequently used to promote targeted protein degradation. The standard protocol for their synthesis involves nucleophilic aromatic substitution of 4-fluorothalidomide with a PEG-amine. We report herein the identification of a commonly ignored

• contamination. Keywords: glutarimide; IMiD; impurity; nucleophilic acyl substitution; PROTAC; Introduction Targeted protein degradation capitalizing on the concept of chemically induced dimerization has emerged as a new therapeutic approach recently [1]. In particular, the modularity of proteolysis targeting

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

• evolves [3]. Complex chemical scaffolds with more than one protein-engaging functionality in a single molecule are advantageous for selectivity. This concept of synergistic compounds and complex chemical interactions helps to boost biological activity and prolongs the emergence of resistance in pathogens

Antibiofilm and cytotoxic metabolites from the entomopathogenic fungus Samsoniella aurantia

• Rita Toshe,
• Syeda J. Khalid,
• Blondelle Matio Kemkuignou,
• Esteban Charria-Girón,
• Paul Eckhardt,
• Birthe Sandargo,
• Kunlapat Nuchthien,
• J. Jennifer Luangsa-ard,
• Till Opatz,
• Hedda Schrey,
• Sherif S. Ebada and
• Marc Stadler

Beilstein J. Org. Chem. 2025, 21, 327–339, doi:10.3762/bjoc.21.23

• Information File 1), it is likely that the activity of farinosones D (1) and A (2) does not interfere with the factors essential for fibronectin binding, particularly the fibronectin-binding proteins such as fibronectin binding protein (FnBPA and B) [18]. FnBPs are adhesions and are known to play a key role