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

• pancreatic carcinoma and triple-negative breast cancer (Scheme 23B) [55]. Konteatis et al. adopted a similar approach by using the direct fusion for the preparation of bisdifluorocyclic biguanides as IDH1/2 inhibitor intermediates (Scheme 23C) [56]. However, sodium dicyanamide has been mainly used as an

• reaction by using hydroxylamine as a nucleophile to substitute the thiomethyl group, followed by pyrrolidine addition on the cyano group to form the corresponding hydroxybiguanidine that was used as an IDO-1 inhibitor (Scheme 37) [77]. In conclusion, despite the obvious synthetic constraints such as the

Application of the Meerwein reaction of 1,4-benzoquinone to a metal-free synthesis of benzofuropyridine analogues

• Rashmi Singh,
• Tomas Horsten,
• Rashmi Prakash,
• Swapan Dey and
• Wim Dehaen

Beilstein J. Org. Chem. 2021, 17, 977–982, doi:10.3762/bjoc.17.79

• cancer cell lines [12][13]. Fluoroquinophenoxazines 2 have been used as telomerase inhibitors in anticancer research [14]. Furthermore, benzofuroisoindoles 3 were part of a kinase inhibitor study [15]. Photobiologically active psoralene (linear furocoumarin) dibenzofurans 1 and angular furanocoumarin

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• produced 90. Similarly, the reaction of 91 produced all-cis-2,3,6-trisubstituted tetrahydropyran 93. The application of this reaction was further extended by an exceptionally concise formal total synthesis of the nuclear export inhibitor (+)-ratjadone A, as shown in Scheme 20. Stereoselective Prins

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• attributes, nuclease stability, and hybridization to single and double stranded nucleic acid targets have led to studies to investigate 3'-NP DNA for antisense and antigene purposes. For example, as an antisense agent in the treatment of human leukemia [67], as an inhibitor of transcription elongation

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• atorvastatin, a potent HMG-CoA reductase inhibitor. Dömling and co-workers efficiently demonstrated an Ugi-based MCR approach towards the synthesis of atorvastatin in four steps ruling out the lengthy seven step protocol, and paving a rapid entry to the drug discovery market [12]. Alternatively, microwave

• double bonds. Numerous natural compounds containing pyrans and benzopyrans (fused pyrans) are identified. Epicalyxin (45) is used as an anticancer agent against human HT-1080 fibrosarcoma and murine 26-L5 carcinoma. Laninamivir (46) is a pyran-based drug used as a neuraminidase inhibitor and zanamivir

β-Lactamase inhibition profile of new amidine-substituted diazabicyclooctanes

• Zafar Iqbal,
• Lijuan Zhai,
• Yuanyu Gao,
• Dong Tang,
• Xueqin Ma,
• Jinbo Ji,
• Jian Sun,
• Jingwen Ji,
• Yuanbai Liu,
• Rui Jiang,
• Yangxiu Mu,
• Lili He,
• Haikang Yang and
• Zhixiang Yang

Beilstein J. Org. Chem. 2021, 17, 711–718, doi:10.3762/bjoc.17.60

• therapy employs the combination of an existing antibiotic with a β-lactamase inhibitor (BLI). A few of BLI/BL combinations have been approved [6] so far for clinical applications by different countries, clavulanic acid/amoxicillin (augmentin) [7][8][9] being the first one, while others are in clinical

• led the researchers to develop second generation β-lactamase inhibitors, finally succeeded with the approval of avibactam and relebactam as non-β-lactam-based BLIs. Avibactam proved potent as inhibitor of Klebsiella pneumoniae carbapenemases (KPCs), AmpCs and some of class D β-lactamases [18] is now

• different kinds of substituents (R) introduced in the final compounds A1–23 are depicted in Table 1. In vitro antibacterial activities of compounds A1–23 were determined first without combining the compounds with an antibacterial drug and the minimum inhibitor concentration (MIC) of each compound was

Effective microwave-assisted approach to 1,2,3-triazolobenzodiazepinones via tandem Ugi reaction/catalyst-free intramolecular azide–alkyne cycloaddition

• Maryna O. Mazur,
• Oleksii S. Zhelavskyi,
• Eugene M. Zviagin,
• Svitlana V. Shishkina,
• Vladimir I. Musatov,
• Maksim A. Kolosov,
• Elena H. Shvets,
• Anna Yu. Andryushchenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2021, 17, 678–687, doi:10.3762/bjoc.17.57

• high anticonvulsant activity after tests in silico and in vivо [7]. Moreover, compounds C and D reveal high activity as casein kinase 2 (CK2) inhibitor and high antitumor activity which makes compounds to be promising anticancer drugs [8]. There are quite a few methods for the synthesis of the

The synthesis of chiral β-naphthyl-β-sulfanyl ketones via enantioselective sulfa-Michael reaction in the presence of a bifunctional cinchona/sulfonamide organocatalyst

• Deniz Tözendemir and
• Cihangir Tanyeli

Beilstein J. Org. Chem. 2021, 17, 494–503, doi:10.3762/bjoc.17.43

• inhibitor activity [33]. Due to the shown biological attractiveness of those 1,3-biarylsulfanyl derivatives, the enantioenriched products can serve as important building blocks for new drugs. The sulfide moiety of β-naphthyl-β-sulfanyl ketones can be oxidized to form sulfones. Despite that sulfones were

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• molecule libraries against a bacterial TGase, an iminocyclitol was conjugated with a pyrophosphate mimic. After in situ screening, the first potent iminocyclitol-based inhibitor against bacterial TGases was efficiently developed [27]. The synthesis of N-pyrrolidine-derived β-phosphonodepsipeptides 64 is

• the macrocyclic phosphonodepsipeptide backbone closely approximated that of the lead inhibitor and showed the low-energy conformation accommodated in the active site of penicillopepsin without significant distortion (Scheme 34) [54]. Synthesis of γ-phosphonodepsipeptides The acyloxyalkyl esters 194

• general method to prepare these compounds [58]. (R)-1-Amino-3-methylbutylphosphonic acid ((R)-204), a phosphonic ʟ-Leu analogue, is a potent inhibitor of the metalloenzyme leucine aminopeptidase. Racemic dibenzyl 1-hydroxy-3-methylbutylphosphonate (203), an oxyanalog of phosphonic leucine, was partially

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• inhibitor screening can be expected. In the field of 19F NMR protein conformational studies another area that has seen increasing attention is that of membrane proteins (MPs). Despite their physiological importance, analysis of the structural biology of MPs is significantly limited due to difficulties

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

Novel library synthesis of 3,4-disubstituted pyridin-2(1H)-ones via cleavage of pyridine-2-oxy-7-azabenzotriazole ethers under ionic hydrogenation conditions at room temperature

• Romain Pierre,
• Anne Brethon,
• Sylvain A. Jacques,
• Aurélie Blond,
• Sandrine Chambon,
• Sandrine Talano,
• Catherine Raffin,
• Branislav Musicki,
• Claire Bouix-Peter,
• Loic Tomas,
• Gilles Ouvry,
• Rémy Morgentin,
• Laurent F. Hennequin and
• Craig S. Harris

Beilstein J. Org. Chem. 2021, 17, 156–165, doi:10.3762/bjoc.17.16

• investment in route scouting and optimization. This full paper focuses on the synthesis issues that we encountered during our route exploration and the original solutions we found that helped us to identify two optimized library-style processes to prepare our large kinase inhibitor library. Keywords: 7

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• iminosugar derivatives may be less obvious. Several pharmaceuticals are based on this scaffold including the glucose-derived nojirimycin, an antibiotic and glycosidase inhibitor [26] and 1-deoxygalactonojirimycin, known under the trade name Galafold®, which is utilized for the treatment of the Fabry disease

Synthesis of aryl 2-bromo-2-chloro-1,1-difluoroethyl ethers through the base-mediated reaction between phenols and halothane

• Yukiko Karuo,
• Ayaka Kametani,
• Atsushi Tarui,
• Kazuyuki Sato,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2021, 17, 89–96, doi:10.3762/bjoc.17.9

• as monofluorinated and trifluoromethylated arenes or aliphatics [1][2][3][4]. Recent progress in difluoromethylene chemistry successfully led to the finding of bioactive compounds such as pantoprazole, a proton pump inhibitor [5], and AFP-07, a prostaglandin I2 receptor-selective agonist [6][7][8

Molecular basis for protein–protein interactions

• Brandon Charles Seychell and
• Tobias Beck

Beilstein J. Org. Chem. 2021, 17, 1–10, doi:10.3762/bjoc.17.1

• strength dependence is β-lactamase and its protein inhibitor BLIP, where binding decreases significantly as the salt concentration increases [53]. Chen et al. analysed the structural and thermodynamic data of 113 heterodimeric complexes and discussed the correlation between binding affinity and amount of

Chemical constituents of Chaenomeles sinensis twigs and their biological activity

• Joon Min Cha,
• Dong Hyun Kim,
• Lalita Subedi,
• Zahra Khan,
• Sang Un Choi,
• Sun Yeou Kim and
• Chung Sub Kim

Beilstein J. Org. Chem. 2020, 16, 3078–3085, doi:10.3762/bjoc.16.257

• synthase (NOS) inhibitor ʟ-NMMA was employed. Graded sodium nitrite solutions were utilized to determine the nitrite concentrations. An MTT assay was used for the cell viability assay. Nerve growth factor and cell viability assays. Analogous as described in [13]. The C6 glioma cells (Korean Cell Line Bank

Secondary metabolites of Bacillus subtilis impact the assembly of soil-derived semisynthetic bacterial communities

• Heiko T. Kiesewalter,
• Carlos N. Lozano-Andrade,
• Mikael L. Strube and
• Ákos T. Kovács

Beilstein J. Org. Chem. 2020, 16, 2983–2998, doi:10.3762/bjoc.16.248

• ][44]. It is presumed that the antifungal plipastatin, expressed from the ppsA-E gene cluster, acts as an inhibitor of phospholipase A2, forming pores in the fungal membrane and causing morphological changes in the fungal membrane and cell wall [45][46]. This antifungal potential was demonstrated

Selected peptide-based fluorescent probes for biological applications

• Debabrata Maity

Beilstein J. Org. Chem. 2020, 16, 2971–2982, doi:10.3762/bjoc.16.247

• cationic fluorescent peptidic β-tryptase inhibitor (peptide 9, Figure 8) [51]. The peptide is designed by attaching two Lys–Trp–Lys tripeptide units to a central lysine via the C-terminus. The N-terminus of both sides are functionalized with pyrenes. Peptide 9 exhibits pyrene monomer emission at 400 nm and

• . Thus, it acts as inhibitor by preventing the substrate to reach the active sites in β-tryptase. Confocal laser scanning microscopy (CLSM) confirms that peptide 9 is mast-cell permeable and exhibits inhibitory activity within cells by suppressing their growth (Figure 8B). Heparin detection Heparin is a

• laser scanning microscopy images of CHMAS cells treated with 10 μM peptide 9 for 30 min. Reproduced from [51], “A fluorescent light-up probe as an inhibitor of intracellular β-tryptase”, © 2014 Wang et al., licensed under a Creative Commons Attribution 3.0 Unported Licence, https://creativecommons.org

Synthesis of imidazo[1,5-a]pyridines via cyclocondensation of 2-(aminomethyl)pyridines with electrophilically activated nitroalkanes

• Dmitrii A. Aksenov,
• Nikolai A. Arutiunov,
• Vladimir V. Maliuga,
• Alexander V. Aksenov and
• Michael Rubin

Beilstein J. Org. Chem. 2020, 16, 2903–2910, doi:10.3762/bjoc.16.239

• synthesis inhibitor (Figure 1) [10][11][12]. In addition, compounds with this structure were investigated as photoluminescent sensors [13] and have been employed to generate pincer and heterocyclic carbene ligands for transition metal catalysis [14][15]. A lot of efforts have been dedicated to the

Nocarimidazoles C and D, antimicrobial alkanoylimidazoles from a coral-derived actinomycete Kocuria sp.: application of ¹J_C,H coupling constants for the unequivocal determination of substituted imidazoles and stereochemical diversity of anteisoalkyl chains in microbial metabolites

• Md. Rokon Ul Karim,
• Enjuro Harunari,
• Amit Raj Sharma,
• Naoya Oku,
• Kazuaki Akasaka,
• Daisuke Urabe,
• Mada Triandala Sibero and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 2719–2727, doi:10.3762/bjoc.16.222

• actinomycete origin. For example, salinosporamide A, an antitumor drug candidate in clinical trials, is a proteasome inhibitor with an unusual γ-lactam-β-lactone bicyclic core produced by marine Salinospora tropica [10]. Abyssomicin, another example of uncommon polycyclic frameworks, is an antibacterial

Asymmetric Mannich reactions of (S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines with yne nucleophiles

• Ziyi Li,
• Li Wang,
• Yunqi Huang,
• Haibo Mei,
• Hiroyuki Konno,
• Hiroki Moriwaki,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2020, 16, 2671–2678, doi:10.3762/bjoc.16.217

• contains the trifluoromethylpropargylamine moiety and has been developed as the inhibitor against non-nucleoside reverse transcriptase for the treatment of human immunodeficiency virus [27] (Figure 1). Thus, the development of synthetic methods for the preparation of these compounds, featuring

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

• complete inhibition of BACE-1 under the conditions of the assay, giving an IC50 value of 59.2 μM. In contrast, analog 2 was a much weaker inhibitor of BACE-1, failing to achieve complete inhibition, and giving an estimated IC50 value of >1,000 μM. There are several conceivable explanations for the reversed

Water-soluble host–guest complexes between fullerenes and a sugar-functionalized tribenzotriquinacene assembling to microspheres

• Si-Yuan Liu,
• Xin-Rui Wang,
• Man-Ping Li,
• Wen-Rong Xu and
• Dietmar Kuck

Beilstein J. Org. Chem. 2020, 16, 2551–2561, doi:10.3762/bjoc.16.207

• attention for potential applications in host–guest recognition, such as gas storage and cationic complexation [31][32][33]. In the past years, the recognition of the biological and pharmaceutical relevance of fullerenes, such as their photodynamic activity, phototoxicity, HIV-1 protease inhibitor ability

NMR Spectroscopy of supramolecular chemistry on protein surfaces

• Peter Bayer,
• Anja Matena and
• Christine Beuck

Beilstein J. Org. Chem. 2020, 16, 2505–2522, doi:10.3762/bjoc.16.203

• multimeric proteins like the hexameric AAA+ ATPase p97 [124]. Furthermore, methyl-TROSY-HMQC has been employed to investigate the allosteric mode of action of the synthetic inhibitor filibuvir to the selectively Ileδ1 methyl-labeled hepatitis C virus RNA polymerase NS5B [125]. This study also includes a good

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

• Benjamin Jeffries,
• Zhong Wang,
• Robert I. Troup,
• Anaïs Goupille,
• Jean-Yves Le Questel,
• Charlene Fallan,
• James S. Scott,
• Elisabetta Chiarparin,
• Jérôme Graton and
• Bruno Linclau

Beilstein J. Org. Chem. 2020, 16, 2141–2150, doi:10.3762/bjoc.16.182

• ][20][21][22]. However, there is comparatively less precedence of lipophilicity comparisons between fluorinated isopropyl groups, cyclopropanes and oxetanes. Examples of bioactive compounds are given in Figure 2. During the optimization of the LpxC inhibitor 7a [23], it was shown that fluorination to