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

A novel spirocyclic scaffold accessed via tandem Claisen rearrangement/intramolecular oxa-Michael addition

• Anastasia Vepreva,
• Alexander Yanovich,
• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1649–1655, doi:10.3762/bjoc.18.177

• arylidene succinimides; intramolecular oxa-Michael addition; rhodium(II) carbene O–H insertion; spirocycles; Introduction Spirocycles undoubtedly occupy a special place in drug design [1] and, in general, spirocyclic compounds intended for the interrogation of biological targets have been associated with

Formal total synthesis of macarpine via a Au(I)-catalyzed 6-endo-dig cycloisomerization strategy

• Jiayue Fu,
• Bingbing Li,
• Zefang Zhou,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2022, 18, 1589–1595, doi:10.3762/bjoc.18.169

• Jiayue Fu Bingbing Li Zefang Zhou 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

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• , amongst many other uses, provided the background for fragment-based drug design [2][3]. – An ever-increasing computer processing speed leading to an ever-growing list of software-based approaches to try to help in various aspects of drugs discovery. The neural network-based software AlphaFold [4], which

• model of infection. Of note is that the hit to lead process was undertaken by the Centre for Drug Design and Discovery and it resulted in a portfolio of patents assigned to Janssen and the catholic university of Leuven [201][202][203]. Interestingly, these patents are protecting a truly original class

Facile and diastereoselective arylation of the privileged 1,4-dihydroisoquinolin-3(2H)-one scaffold

• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1070–1078, doi:10.3762/bjoc.18.109

• associated biological activities and relevance to the naturally occurring alkaloids [1], 1,4-dihydro-3(2H)-isoquinolones (1,4-DHIQs) undoubtedly represent a privileged scaffold [2] for drug design considering such diversely bioactive compounds documented in the literature as ligand for serotonin 5-HT1A

Synthesis and HDAC inhibitory activity of pyrimidine-based hydroxamic acids

• Virginija Jakubkiene,
• Gabrielius Ernis Valiulis,
• Markus Schweipert,
• Asta Zubriene,
• Daumantas Matulis,
• Franz-Josef Meyer-Almes and
• Sigitas Tumkevicius

Beilstein J. Org. Chem. 2022, 18, 837–844, doi:10.3762/bjoc.18.84

• Engineering and Biotechnology, University of Applied Sciences, Stephanstr. 7, 64295 Darmstadt, Germany Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Sauletekio 7, 10257 Vilnius, Lithuania 10.3762/bjoc.18.84 Abstract Histone deacetylases

Cholyl 1,3,4-oxadiazole hybrid compounds: design, synthesis and antimicrobial assessment

• Anas J. Rasras,
• Mohamed El-Naggar,
• Nesreen A. Safwat and
• Raed A. Al-Qawasmeh

Beilstein J. Org. Chem. 2022, 18, 631–638, doi:10.3762/bjoc.18.63

• the development of multidrug resistant bacteria due to excessive use of antibiotics [2][4]. Heterocyclic compounds are the key components for drug design and synthesis. Among them, 1,3,4-oxadiazole derivatives are attractive and have been investigated for decades. This is due to their promising

Unexpected chiral vicinal tetrasubstituted diamines via borylcopper-mediated homocoupling of isatin imines

• Marco Manenti,
• Leonardo Lo Presti,
• Giorgio Molteni and
• Alessandra Silvani

Beilstein J. Org. Chem. 2022, 18, 303–308, doi:10.3762/bjoc.18.34

• -butanesulfinyl ketimine; homocoupling; Introduction As bioisosteres of carboxylic acid derivatives, boronic acids have recently emerged as a novel chemotype in drug design, with a number of boron-containing compounds recently being approved by the FDA [1][2][3][4]. In particular, α- and β-aminoboronic acids are

Synthesis of 1-indolyl-3,5,8-substituted γ-carbolines: one-pot solvent-free protocol and biological evaluation

• Premansh Dudhe,
• Mena Asha Krishnan,
• Kratika Yadav,
• Diptendu Roy,
• Krishnan Venkatasubbaiah,
• Biswarup Pathak and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2021, 17, 1453–1463, doi:10.3762/bjoc.17.101

• purification reduce the efforts in the synthesis of complex molecular architectures. Therefore, cascade reactions are essential in synthetic organic chemistry, even with moderate yields [26]. Recently, such reactions have claimed their much deserving place in drug design and natural product synthesis [27]. In

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• -driven research led to a large production of standard every-day drugs with antidiabetic, antiseptic, and even anticancer properties. Recently, biguanides have gained particularly increasing attention in several areas, such as drug design, coordination chemistry, and materials science [1]. In this context

Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

• Yamato Fujihira,
• Yumeng Liang,
• Makoto Ono,
• Kazuki Hirano,
• Takumi Kagawa and
• Norio Shibata

Beilstein J. Org. Chem. 2021, 17, 431–438, doi:10.3762/bjoc.17.39

• of fluorine(s) into organic molecules usually leads to significant changes in the chemical and physicochemical properties of the original compounds [5][6]. Hence, the fluorination and related fluoro-functionalization of drug candidates are powerful strategies in drug design to appropriately bias

Hydrazides in the reaction with hydroxypyrrolines: less nucleophilicity – more diversity

• Dmitrii A. Shabalin,
• Evgeniya E. Ivanova,
• Igor A. Ushakov,
• Elena Yu. Schmidt and
• Boris A. Trofimov

Beilstein J. Org. Chem. 2021, 17, 319–324, doi:10.3762/bjoc.17.29

• fragments of influenza neuraminidase inhibitors [1], nonsteroidal progesterone receptor regulators [2][3], anti-inflammatory [4], antihypertensive and spasmolytic [5][6][7] agents (Figure 1). It is due to their prospects in drug design that a search for effective synthetic protocols to construct partially