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

• systems significantly enhances its hydrogen bond donation ability, a result consistent with theoretical calculations. We anticipate that this chemistry will be valuable for designing functional molecules for chemical biology and medicinal chemistry applications. Keywords: bioisostere; difluoromethyl

• 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

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

• , commonly referred to as sulfa drugs. These include top seller drugs, e.g., antimicrobials, anti-inflammatories, antihypertensives, and antitumor agents [24][25][26]. Particularly, the sulfonamide motif can act as a bioisostere of carboxylic acids, establishing a set of hydrogen bonds similar to those

Direct trifluoroethylation of carbonyl sulfoxonium ylides using hypervalent iodine compounds

• Radell Echemendía,
• Carlee A. Montgomery,
• Fabio Cuzzucoli,
• Antonio C. B. Burtoloso and
• Graham K. Murphy

Beilstein J. Org. Chem. 2024, 20, 3182–3190, doi:10.3762/bjoc.20.263

• -containing functional groups, the 2,2,2-trifluoroethyl group (CF3CH2), is gaining significant interest from synthetic chemists. This is due to its reduced electron-withdrawing aspect compared to the CF3 group, its larger steric bulk and increased polarity. This moiety is also considered as a bioisostere of

Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• has become an essential structural motif in medicinal chemistry due to its hydrogen-bond donor capacity, its lipophilic character, and as a bioisostere for alcohol, thiol, or amine groups [16][17][18][19]. Thus, the contribution of fluorinated compounds to pharmaceuticals has been crucial for more

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• agrochemicals has been shown to greatly increase the potency of a compound [45][46] and can be considered a bioisostere for a methyl group. Chlorination through HVI approaches provides a safe and mild approach to chlorinated cyclic compounds. Nitrogen nucleophiles Intramolecular chlorocyclisation promoted by

Synthesis of fluoroalkenes and fluoroenynes via cross-coupling reactions using novel multihalogenated vinyl ethers

• Yukiko Karuo,
• Keita Hirata,
• Atsushi Tarui,
• Kazuyuki Sato,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2024, 20, 2691–2703, doi:10.3762/bjoc.20.226

• Fluoroalkenes are one of the important frameworks for a wide range of industrial fields. For example, they are used as a bioisostere of amide bonds in medicines and agrochemicals, and contribute to the synthesis of peptide medicines that are stable to enzymatic metabolism and possess high lipophilicity [1]. In

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• Carlos Nieto Alejandro Manchado Angel Garcia-Gonzalez David Diez Narciso M. Garrido Department of Organic Chemistry, Faculty of Chemical Sciences, University of Salamanca, Pl. Caídos, s/n, 37008 Salamanca, Spain 10.3762/bjoc.20.163 Abstract The concept of bioisostere replacement is of paramount

• -ring bioisostere, but as carboxylic acid one, Schwarz et al. [79] developed tetrazole-based pregabalin bioisosteres 113–118 (Scheme 18). The target protein α2-δ is involved in neurotransmitters release reduction, as a model of anxiety and neuropathic pain. In general, submicromolar affinities were

• systems reveals a conserved pattern: most of the changes are related to bioisostere structure–activity exploration of the chemical space from original phenyl hits. The results with the imidazole analogues are different, since the ʟ-histidine unit marks a non-phenyl-based scaffold hopping. The main goal of

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

• Institute, Palackӯ University in Olomouc, Olomouc, Czech Republic 10.3762/bjoc.20.85 Abstract Tetrazole is widely utilized as a bioisostere for carboxylic acid in the field of medicinal chemistry and drug development, enhancing the drug-like characteristics of various molecules. Typically, tetrazoles are

• ready-to-screen drug-like molecules remains a key challenge in the medicinal chemistry field [5][6]. Tetrazole is considered as a privileged scaffold in pharmaceutical and medicinal chemistry, used as a carboxylic acid bioisostere and a cis-amide mimic contributing to improvements in lipophilicity

• due to the protected nature of the tetrazol. Additionally, inclusion of a strategically placed tetrazole and bioisostere replacement of MCR substrate with tetrazole may give rise to molecules with improved drug-like characteristics with nominal weight or size difference. This tetrazole building block

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• benzenes that have more than one substituent; for example, the ortho-, meta-, or para- relative substitution of a disubstituted benzene should ideally be replicated in the saturated bioisostere to ensure ligand–protein binding is conserved through the bioisosteric swap. Bioisosteres of para-substituted

• benzenes are by now relatively well established. Cubanes [16][17], alkynes [18], and bicyclo[2.2.2]octanes [19] can all replicate the linear geometry of the para-substituents, but arguably the most well-investigated para-benzene bioisostere is bicyclo[1.1.1]pentane (BCP) [20][21][22][23] (Figure 1). The

• each method, enabling practitioners to quickly find the bioisostere and method that best suits their requirements. Physiochemical and biological data will also be discussed where available. Review Definitions and parameters for determination of (bio)isosterism We will distinguish between geometric

Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors

• Jens Frackenpohl,
• David M. Barber,
• Guido Bojack,
• Birgit Bollenbach-Wahl,
• Ralf Braun,
• Rahel Getachew,
• Sabine Hohmann,
• Kwang-Yoon Ko,
• Karoline Kurowski,
• Bernd Laber,
• Rebecca L. Mattison,
• Thomas Müller,
• Anna M. Reingruber,
• Dirk Schmutzler and
• Andrea Svejda

Beilstein J. Org. Chem. 2024, 20, 540–551, doi:10.3762/bjoc.20.46

• -dihydro[1,3]thiazolo[4,5-b]pyridine; acyl-ACP thioesterase; bioisostere; herbicide; heterocycle; Introduction The presence of weed infestations exerts a high strain on food production around the globe by depleting resources for the crops and facilitating the transmission of diseases [1]. Although

Recent advancements in iodide/phosphine-mediated photoredox radical reactions

• Tinglan Liu,
• Yu Zhou,
• Junhong Tang and
• Chengming Wang

Beilstein J. Org. Chem. 2023, 19, 1785–1803, doi:10.3762/bjoc.19.131

• bioisostere for a range of functional groups (such as CH2OH, CH2OCH3, CH2NH2, and CH2SH). Among the various methods available, radical-involving cross-couplings have proven to be the most effective [48][49]. However, the generation of the CH2F radical remains to be a challenging task. Therefore, there is an

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

• indispensable role in drug discovery and design since the hydrogen atom can act as lipophilic hydrogen-bond donor and act as a bioisostere for the alcohol moiety [81][82][83]. Thus, many effective difluoromethylation strategies have been developed in recent years. Difluoroacetohydrazonoyl bromides were chosen

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• serve as bioisostere for aromatic rings, amines, amides, and N-containing heterocycles. Due to the aforementioned qualities, numerous U.S. FDA-approved medications have pyridine scaffolds in their molecules (Figure 1). In this context, the synthesis of the pyridine motif is always there in trend. Many

New triazole-substituted triterpene derivatives exhibiting anti-RSV activity: synthesis, biological evaluation, and molecular modeling

• Elenilson F. da Silva,
• Krist Helen Antunes Fernandes,
• Denise Diedrich,
• Jessica Gotardi,
• Marcia Silvana Freire Franco,
• Carlos Henrique Tomich de Paula da Silva,
• Ana Paula Duarte de Souza and
• Simone Cristina Baggio Gnoatto

Beilstein J. Org. Chem. 2022, 18, 1524–1531, doi:10.3762/bjoc.18.161

• metabolite of RBV, leading to GTP depletion, since best poses achieved for the tested compound interact in an equivalent way as IMP and inhibitor MAD1 and in the same site of action, suggesting that compound 8 can be a bioisostere for IMPDH inhibitors that could be used to combat RSV infections. However

Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction

• Dušan Đ. Škorić,
• Olivera R. Klisurić,
• Dimitar S. Jakimov,
• Marija N. Sakač and
• János J. Csanádi

Beilstein J. Org. Chem. 2021, 17, 2611–2620, doi:10.3762/bjoc.17.174

• bile acids, derivatives with altered hydrophobicity are being studied [12][13][14]. The tetrazole moiety can be found in many biologically active compounds, and monosubstituted tetrazole is being used in medicinal chemistry as a bioisostere of carboxylic acid [15] because it increases the lipophilicity

Chemical synthesis of C6-tetrazole ᴅ-mannose building blocks and access to a bioisostere of mannuronic acid 1-phosphate

• Eleni Dimitriou and
• Gavin J. Miller

Beilstein J. Org. Chem. 2021, 17, 1527–1532, doi:10.3762/bjoc.17.110

• approach to provide structurally defined building blocks containing bioisosteres of ᴅ-mannuronic acid. Building on our recently reported synthesis and glycosylation capability of hydroxamate-modified ᴅ-mannuronate building blocks [11], we now demonstrate the synthesis of a second carboxylate C6-bioisostere

• , tetrazole (Figure 1b). As an established bioisostere for a carboxylic acid, tetrazole has found significant application within medicinal chemistry [12]. The aromatic tetrazole ring is considered a non-classical bioisostere, differing in size and number of atoms to the carboxylic acid. The functional group

• 5.41 ppm [dd, J = 7.9, 1.7 Hz, H1]) supported an α-linked manno 1-phosphate derivative. This material complimented our recently reported C6-hydroxamic acid derivative as a bioisostere for mannuronic acid 1-phosphate [20], and will be enabling for evaluating non-native glycosyl 1-phosphates in

Vicinal difluorination as a C=C surrogate: an analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity

• Yuvixza Lizarme-Salas,
• Alexandra Daryl Ariawan,
• Ranjala Ratnayake,
• Hendrik Luesch,
• Angela Finch and
• Luke Hunter

Beilstein J. Org. Chem. 2020, 16, 2663–2670, doi:10.3762/bjoc.16.216

• for E-alkenes in medicinal chemistry. Keywords: Alzheimer's disease; bioisostere; conformational analysis; gauche effect; stereoselective synthesis; Introduction Piperine (1, Figure 1) is a well-known natural product that is derived from peppercorns [1][2][3]. Many biological studies of 1 have been

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• = 1.20 Å) [9][14], the fluorine atom is often used as a bioisostere for the hydrogen atom. Furthermore, the trifluoromethyl group was recently identified as a bioisostere for the nitro (NO2) group, which is important due to the strong binding ability of the nitro group and the high reactivity, which is

Microwave-assisted efficient one-pot synthesis of N²-(tetrazol-5-yl)-6-aryl/heteroaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines

• Moustafa Sherief Moustafa,
• Ramadan Ahmed Mekheimer,
• Saleh Mohammed Al-Mousawi,
• Mohamed Abd-Elmonem,
• Hesham El-Zorba,
• Afaf Mohamed Abdel Hameed,
• Tahany Mahmoud Mohamed and
• Kamal Usef Sadek

Beilstein J. Org. Chem. 2020, 16, 1706–1712, doi:10.3762/bjoc.16.142

• ]. Tetrazole derivatives are a potent class of heterocyclic compounds with a wide range of biological activities owing to their unique structure. They play an important role not only as a bioisostere of the carboxylic acid group but also as flexible ligands which easily adopt to different binding modes [12][13

Fluorohydration of alkynes via I(I)/I(III) catalysis

• Jessica Neufeld,
• Constantin G. Daniliuc and
• Ryan Gilmour

Beilstein J. Org. Chem. 2020, 16, 1627–1635, doi:10.3762/bjoc.16.135

• fluorine as a powerful physicochemical modulator in small-molecule drug discovery is a compelling argument for the importance of sustained innovation to facilitate this form of structural editing [1][2][3][4]. Routinely employed as a bioisostere of hydrogen or hydroxy [5][6], substitution may enable

Copper-based fluorinated reagents for the synthesis of CF₂R-containing molecules (R ≠ F)

• Louise Ruyet and
• Tatiana Besset

Beilstein J. Org. Chem. 2020, 16, 1051–1065, doi:10.3762/bjoc.16.92

• -generated copper-based CF2PO(OEt)2 reagent As a bioisostere of the phosphonate group [47], a lot of attention was paid to the difluoromethylphosphonate residue as well as the development of efficient methodologies to introduce it onto molecules [48]. In that context, main contributions were made by the

Fluorocyclisation via I(I)/I(III) catalysis: a concise route to fluorinated oxazolines

• Felix Scheidt,
• Christian Thiehoff,
• Gülay Yilmaz,
• Stephanie Meyer,
• Constantin G. Daniliuc,
• Gerald Kehr and
• Ryan Gilmour

Beilstein J. Org. Chem. 2018, 14, 1021–1027, doi:10.3762/bjoc.14.88

• -ray crystallographic analysis of a representative example. Given the importance of fluorine in drug discovery, its ability to modulate conformation, and the prevalence of the 2-oxazoline scaffold in Nature, this strategy provides a rapid entry into an important bioisostere class. Keywords: catalysis

• ]. Since hydrogen and hydroxy groups are often substituted by fluorine in molecular editing processes [12], this transformation would provide facile access to a bioisostere of the parent scaffold (Figure 1, right). In recent years, I(I)/I(III) catalysis has emerged as a powerful and expansive platform for

• corresponding 1,2-difluoroethylene unit; a substructure that may be considered a chiral, hybrid bioisostere of the Et and CF3 groups (Figure 2, top) [36]. Since the success of this process is contingent on the efficient generation of p-TolIF2 in situ, the platform lends itself to related oxidative

Ring-size-selective construction of fluorine-containing carbocycles via intramolecular iodoarylation of 1,1-difluoro-1-alkenes

• Takeshi Fujita,
• Ryo Kinoshita,
• Tsuyoshi Takanohashi,
• Naoto Suzuki and
• Junji Ichikawa

Beilstein J. Org. Chem. 2017, 13, 2682–2689, doi:10.3762/bjoc.13.266

• afford difluoromethylated dihydrophenanthrene derivative 4a in almost quantitative yield [29][30]. A difluoromethyl group functions as a hydrogen-bond donor and a bioisostere of a hydroxy group, as a result of which difluoromethyl-bearing compounds attract much attention as bioactive materials [31][32

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

Deoxygenative gem-difluoroolefination of carbonyl compounds with (chlorodifluoromethyl)trimethylsilane and triphenylphosphine

• Fei Wang,
• Lingchun Li,
• Chuanfa Ni and
• Jinbo Hu

Beilstein J. Org. Chem. 2014, 10, 344–351, doi:10.3762/bjoc.10.32

• used in the design of potential enzyme inhibitors [4][5][6], since difluoromethylene functionality (CF2) is known to be isosteric and isopolar to an oxygen atom [7][8][9], and the gem-difluorovinyl functionality is believed to be a bioisostere for a carbonyl group [10]. More commonly, 1,1