Synthesis of the tetracyclic skeleton of Aspidosperma alkaloids via PET-initiated cationic radical-derived interrupted [2 + 2]/retro-Mannich reaction

• Ru-Dong Liu,
• Jian-Yu Long,
• Zhi-Lin Song,
• Zhen Yang and
• Zhong-Chao Zhang

Beilstein J. Org. Chem. 2025, 21, 2470–2478, doi:10.3762/bjoc.21.189

• Education and Beijing National Laboratory for Molecular Science, and Peking-Tsinghua Centre for Life Sciences, Peking University, Beijing 100871, China Shenzhen Bay Laboratory, Shenzhen 518055, China Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical

• Science-Shenzhen Fundamental Research Institutions (2024SHIBS0004), Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical Universit (SY2024KF-02), the research grants from the Major Program of Shenzhen Bay Laboratory, and the Shenzhen Outstanding

Pathway economy in cyclization of 1,n-enynes

• Hezhen Han,
• Wenjie Mao,
• Bin Lin,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2025, 21, 2260–2282, doi:10.3762/bjoc.21.173

• Hezhen Han Wenjie Mao Bin Lin Maosheng Cheng Lu Yang Yongxiang Liu Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang 110016, P. R. China Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016

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

Understanding the origin of stereoselectivity in the photochemical denitrogenation of 2,3-diazabicyclo[2.2.1]heptene and its derivatives with non-adiabatic molecular dynamics

• Leticia A. Gomes and
• Steven A. Lopez

Beilstein J. Org. Chem. 2025, 21, 2007–2020, doi:10.3762/bjoc.21.156

• chemoselectivity for cysteine alkylation under mild conditions, for example, BCB-ibrutinib [28] (Scheme 1c). BCB is also used as a precursor to byciclo[1.1.1]pentanes, which are valuable motifs in drug design [19][20][29][30][31][32][33], such as BCP-darapladib (Scheme 1c) [30][31][34][35]. Housanes are versatile

[3 + 2] Cycloaddition of thioformylium methylide with various arylidene-azolones in the synthesis of 7-thia-3-azaspiro[4.4]nonan-4-ones

• Daniil I. Rudik,
• Irina V. Tiushina,
• Anatoly I. Sokolov,
• Alexander Yu. Smirnov,
• Alexander R. Romanenko,
• Alexander A. Korlyukov,
• Andrey A. Mikhaylov and
• Mikhail S. Baranov

Beilstein J. Org. Chem. 2025, 21, 1791–1798, doi:10.3762/bjoc.21.141

• bioorganic chemistry [1]. Such substances are actively investigated in drug design, since their rigid 3D structure allows them to bind more selectively and effectively to biological targets in comparison to classical planar heterocycles [1][2][3][4][5]. Spirocyclic derivatives containing at least one five

• would be of help in further drug design of spirocyclic scaffolds. Single crystal X-ray analysis for the compounds 6e (A), 7d (B), 8e (C) and 9e (D). Atoms are shown as thermal ellipsoids at 50% probability. All hydrogen atoms, except the one at the stereogenic center, are omitted for clarity. Synthetic

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

• drug design and therapeutic strategies. Notably, PA derivatives also exhibit specificity in recognizing important molecules in biological processes, such as acetylcholine [80], amino acids [81], doxorubicin (DOX) [82] and antibiotics [83], etc. Among the many derivatives, water-soluble pillar[5]arene

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

• become quite attractive structural motifs in drug design [13][14]. A few examples are shown in Figure 3: oxetano-thalidomide 1 was designed as an analogue of the infamous thalidomide to block racemisation and hence prevent the severe side-effects caused by the opposite enantiomer [15]. Compound 2 is a

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

• relatively new prima donna of functional groups explored in drug design, were smoothly prepared. 2.4 Miscellaneous reactions Cyclopropenone, the smallest Hückel aromatic system, has been subjected to the ring opening reactions, driven by the release of ring strain. Numerous transformations of cyclopropenone

Recent advances in the electrochemical synthesis of organophosphorus compounds

• Babak Kaboudin,
• Milad Behroozi,
• Sepideh Sadighi and
• Fatemeh Asgharzadeh

Beilstein J. Org. Chem. 2025, 21, 770–797, doi:10.3762/bjoc.21.61

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

• valuable property in the context of drug design, because chameleonic fluorinated molecules such as compounds 2 and 3 might be expected to pass more easily through cell membranes, a manoeuvre which requires some level of solubility in both aqueous and organic environments. Another consequence of introducing

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

• was not extracted from background-corrected voltammograms. All CV graphs are plotted using IUPAC polarographic convention. Selected examples of α,α-disubstituted cyclic amino acids in drug design. Electrochemical decarboxylative amination reactions. A) Cyclic voltammograms of 6a and 9a at 3 mM and 6

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

• naturally in mRNA riboswitches in bacteria and is involved in ligand-dependent gene regulation. Therefore, this riboswitch (like others) has become an attractive target for drug design. To date, most known RNA–small molecule binders interact in a non-covalent manner. The compounds presented here are part of

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

• difluoromethylene (PhCF2) group, stand out as particularly valuable in drug design. The CF2H group can serve as a lipophilic isostere for hydroxy (OH), amino (NH2), and thiol (SH) groups, thereby enhancing the efficacy and selectivity of therapeutic agents [4][5][6]. Similarly, the PhCF2 group offers unique

• broader applicability in drug design to some extent. Besides, the incorporation of the PhCF2 group into tricyclic imidazoles has never been reported according to our best knowledge. Therefore, it is essential to explore environmentally friendly, cost-effective synthetic approaches for the construction of

• -effectiveness, position it as a valuable strategy in drug design and the synthesis of fluorinated compounds. Selected examples containing tricyclic imidazole, CF2H or PhCF2 group. Strategies for the synthesis of difluoromethylated and difluoroarylmethylated tricyclic imidazoles. Substrate scope of the protocol

Quantifying the ability of the CF₂H group as a hydrogen bond donor

• Matthew E. Paolella,
• Daniel S. Honeycutt,
• Bradley M. Lipka,
• Jacob M. Goldberg and
• Fang Wang

Beilstein J. Org. Chem. 2025, 21, 189–199, doi:10.3762/bjoc.21.11

• exhibits slower acid dissociation [25] and different lipophilicity [19][20][26][27][28]. For these reasons, it is an attractive synthetic target [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] and an important bioisostere in drug design and biochemical studies [30][44][45][46]. Despite the

Facile one-pot reduction of β-nitrostyrenes to phenethylamines using sodium borohydride and copper(II) chloride

• Laura D’Andrea and
• Simon Jademyr

Beilstein J. Org. Chem. 2025, 21, 39–46, doi:10.3762/bjoc.21.4

• Laura D'Andrea Simon Jademyr Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 København Ø, Denmark current address: Department of Chemistry and Bioscience, Aalborg University, Fredrik Bajers Vej 7H, 9220

Reactivity of hypervalent iodine(III) reagents bearing a benzylamine with sulfenate salts

• Beatriz Dedeiras,
• Catarina S. Caldeira,
• José C. Cunha,
• Clara S. B. Gomes and
• M. Manuel B. Marques

Beilstein J. Org. Chem. 2024, 20, 3281–3289, doi:10.3762/bjoc.20.272

• formed by carboxylic acids, enhancing its versatility and effectiveness in drug design [27]. Traditional sulfonamide preparation involves combining sulfonyl chlorides and amines [25][28][29]. Despite the efficiency of traditional methods, challenges still remain, e.g., use of harsh conditions, like

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

• potential in anticancer drug design. However, it should be taken into account that the sulfonyl group can radically change the pharmacokinetic properties of a drug, so the effect it may have on its ADMET properties should be determined in an additional study. Conclusion A novel synthetic strategy has been

Finding the most potent compounds using active learning on molecular pairs

• Zachary Fralish and
• Daniel Reker

Beilstein J. Org. Chem. 2024, 20, 2152–2162, doi:10.3762/bjoc.20.185

• regimes by enabling faster and more accurate identification of more diverse molecular hits against critical drug targets. Keywords: active learning; drug design; machine learning; molecular optimization; potency predictions; Introduction Active learning is a powerful concept in molecular machine

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

• for humans, animals and plants, including drug design [14][15], vaccine development [15][16] and numerous other possibilities in the field of carbohydrate chemistry and biology. Notably, the regulation of the host immune response is often mediated by glycans, particularly through their recognition by

• effective drug design. Moreover, ab initio prediction of a protein's structure only from its amino acid sequence remains unsolved. Accessing Rosetta molecular modelling software tools (https://www.rosettacommons.org/software) has traditionally required expertise in the Unix command line environment

• superior performance in structural and energetic precision. This method is particularly valuable in drug design involving protein–carbohydrate interactions, addressing weaknesses such as the CH–π interactions that are challenging for other programs like Vina-Carb. 3. FlexX [132][133]: It is a molecular

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• (azetidin-2-one) scaffold to medicinal chemistry and drug design is self-evident. This four-membered heterocycle is a key fragment of many antibiotics [1], including penicillin and its analogues, as well as other pharmacologically important molecules [2]. Therefore, the search for new efficient and

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• Jingyao Li Ajay L. Chandgude Qiang Zheng Alexander Domling Department of Drug Design, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry and Czech Advanced Technology and Research

• . During preclinical research large screening libraries are integral part of the structure-based drug design and high-throughput screening and facile, efficient synthetic methods to explore diverse chemical spaces are of great help [2][3][4]. However, due to the vastness of chemical space, generation of

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

• Alexander Yanovich,
• Anastasia Vepreva,
• Ksenia Malkova,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48

• modern drug design [1][2]. They are known to promote higher success rates, when targeting three-dimensional protein molecules [3][4]. Furthermore, a wide variety of spirocyclic fragments can be spotted in natural products [5]. The aspects mentioned unveil the development of synthetic methodologies

• products. For example, spirocyclic Δα,β-butenolides (furan-2(5H)-ones) represent a valuable class of molecular frameworks for drug design and are abundant in nature [15]. Bioactive naturally occurring spiro Δα,β-butenolides include spirofragilide (with anti-inflammatory, antibiotic, antitumor, anti-HIV

Trifluoromethylated hydrazones and acylhydrazones as potent nitrogen-containing fluorinated building blocks

• Zhang Dongxu

Beilstein J. Org. Chem. 2023, 19, 1741–1754, doi:10.3762/bjoc.19.127

• reactions and indicate their potential offering an efficient approach to fluoroalkylated heterocycles in drug design. Trifluoromethylated acylhydrazonoes Acylhydrazones are a well-established class of organic compounds with the –CONH–N=CH– structure, and some variants show potential pesticidal and

Facile access to 3-sulfonylquinolines via Knoevenagel condensation/aza-Wittig reaction cascade involving ortho-azidobenzaldehydes and β-ketosulfonamides and sulfones

• Ksenia Malkova,
• Andrey Bubyrev,
• Stanislav Kalinin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 800–807, doi:10.3762/bjoc.19.60

• Ksenia Malkova Andrey Bubyrev Stanislav Kalinin Dmitry Dar'in Saint Petersburg State University, Saint Petersburg 199034, Russian Federation 10.3762/bjoc.19.60 Abstract Quinoline-based sulfonyl derivatives, and especially sulfonamides, are relevant and promising structures for drug design. We

• novel quinoline construction and functionalization techniques resulting in new or rare derivatives [17][18][19][20][21][22][23][24][25][26] is an important mission in the field of drug discovery and medicinal chemistry. The sulfonamide group is a known privileged motif in drug design often serving as a

Synthesis and characterisation of new antimalarial fluorinated triazolopyrazine compounds

• Kah Yean Lum,
• Jonathan M. White,
• Daniel J. G. Johnson,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2023, 19, 107–114, doi:10.3762/bjoc.19.11

• of fluorine or a fluorinated functional group into organic compounds has become increasingly prevalent in drug design and development, as fluorine substitution can greatly influence drug potency, pharmacokinetic and pharmacodynamic properties [19]. Therefore, in this study we undertook additional LSF