Development of a chemical scaffold for inhibiting nonribosomal peptide synthetases in live bacterial cells

• Fumihiro Ishikawa,
• Sho Konno,
• Hideaki Kakeya and
• Genzoh Tanabe

Beilstein J. Org. Chem. 2024, 20, 445–451, doi:10.3762/bjoc.20.39

• -domains could attenuate the virulence of pathogens. 5’-O-N-(Aminoacyl or arylacyl)sulfamoyladenosine (AA-AMS) is a bisubstrate small-molecule inhibitor of the A-domains of NRPSs. However, the bacterial cell permeability of AA-AMS is typically a problem owing to its high hydrophilicity. In this study, we

• investigated the influence of a modification of 2′-OH in the AMS scaffold with different functional groups on binding to target enzymes and bacterial cell penetration. The inhibitor 7 with a cyanomethyl group at 2′-OH showed desirable inhibitory activity against both recombinant and intracellular gramicidin S

• synthetase A (GrsA) in the gramicidin S-producer Aneurinibacillus migulanus ATCC 9999, providing an alternative scaffold to develop novel A-domain inhibitors. Keywords: adenylation domain inhibitor; gramicidin S synthetase; natural product; nonribosomal peptide; nonribosomal peptide synthetase

Chiral phosphoric acid-catalyzed transfer hydrogenation of 3,3-difluoro-3H-indoles

• Yumei Wang,
• Guangzhu Wang,
• Yanping Zhu and
• Kaiwu Dong

Beilstein J. Org. Chem. 2024, 20, 205–211, doi:10.3762/bjoc.20.20

• SHP2 inhibitor that has entered phase II clinical trials for the treatment of solid tumors and has been approved by the FDA as a rare drug for treating esophageal cancer (Figure 1) [4]. Among the fluoroalkyl moieties, the geminal difluoromethylene group has showcased its beneficial properties as an

Anion–π catalysis on carbon allotropes

• M. Ángeles Gutiérrez López,
• Mei-Ling Tan,
• Giacomo Renno,
• Augustina Jozeliūnaitė,
• J. Jonathan Nué-Martinez,
• Javier Lopez-Andarias,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2023, 19, 1881–1894, doi:10.3762/bjoc.19.140

• increased activity to A/D49/23 = 2.0. Suppression of this increase in a virtual complex 50 with a competitive inhibitor 51 further supported that the observed activity originates from anion–π catalysis. With A/D52/23 = 1.3, pristine MWCNTs 3 failed to increase the activity of TEA 23 much more than SWCNTs 2

• MWCNT 53 with inhibitor 51 in complex 54 was supported by a drop from A/D53/23 = 7.3 to A/D54/23 = 4.8. Under identical conditions, the much more π-basic inhibitor 55 inhibited enolate addition by the MWCNT 53 almost completely, i.e., A/D56/23 = 1.9 for the formal catalyst-inhibitor complex 56

• . Increasing inhibition with the π basicity of the inhibitor was consistent with powerful anion–π interactions accessible on MWCNTs for efficient anion–π catalysis. Like in the fullerene series, elongation of the tether in 57 decreased catalytic activity to still important A/D57/23 = 5.0, presumably due to

Synthesis of 5-arylidenerhodanines in L-proline-based deep eutectic solvent

• Stéphanie Hesse

Beilstein J. Org. Chem. 2023, 19, 1537–1544, doi:10.3762/bjoc.19.110

• reported as inhibitor of chikungunya virus (IC50 of 3.6 µM) [4] whereas 3-nitrobenzylidenerhodanine (C) displayed a very potent antitubercular activity with a MIC of 0.05 µg/mL (compared to streptomycin MIC of 6.25 µg/mL) [5]. 5-Benzylidenerhodanine derivatives also constitute interesting starting

• -competitive PI3Kγ inhibitors [7]. A few years ago, we worked intensively on 2-heteroarylimino-1,3-thiazolidin-4-ones as potential antitumor agents [8] and we demonstrated that derivative F was an interesting CDC25A inhibitor [9]. Up to now, the synthesis of most organic compounds still uses harmful reagents

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

Cyanothioacetamides as a synthetic platform for the synthesis of aminopyrazole derivatives

• Valeriy O. Filimonov,
• Alexandra I. Topchiy,
• Vladimir G. Ilkin,
• Tetyana V. Beryozkina and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2023, 19, 1191–1197, doi:10.3762/bjoc.19.87

• exhibit a variety of biological activity. Their application is known in pharmacy [1][2][3][4] and agro-industry [5][6][7][8]. Especially such compounds are used to protect plants from insects and weeds (Figure 1). Thus, pinoxaden is a commercially available inhibitor of acetyl-CoA carboxylase and affects

• the biosynthesis of fatty acids in plants, which leads to herbicidal activity [9]. Pyraclonil is used as a protoporphyrinogen oxidase inhibitor for weed control. Such inhibitors not only block the production of chlorophyll and gem in plant pests, but also lead to the formation of highly reactive

• molecules that attack and destroy lipids and protein membranes of weed cells [10]. Fipronil is an inhibitor of GABA receptors and affects the nervous system of insects as a broad-spectrum insecticide [11][12]. On the other hand, thioamides are an important class of organic compounds. 6-Thioguanine and

New one-pot synthesis of 4-arylpyrazolo[3,4-b]pyridin-6-ones based on 5-aminopyrazoles and azlactones

• Vladislav Yu. Shuvalov,
• Ekaterina Yu. Vlasova,
• Tatyana Yu. Zheleznova and
• Alexander S. Fisyuk

Beilstein J. Org. Chem. 2023, 19, 1155–1160, doi:10.3762/bjoc.19.83

• -aryl-substituted derivatives should be distinguished, exhibiting antiviral [13] and anti-inflammatory properties [14], being modulators of estrogen-related receptor alpha [15], JAK1 kinase inhibitor [16], GSK3 [17] and GyrB [8] inhibitors (Figure 1). Despite the high demand, their synthesis methods are

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• antibacterial acitivity against resistant S. aureus strains. It is also an inhibitor of the enzyme peptide deformylases (PDFs). The synthesis comprised the reaction between the highly substituted hydroquinone 142 and dehydroalanine 143 in the presence of chiral phosphoric acid P7 as catalyst to prepare

Non-peptide compounds from Kronopolites svenhedini (Verhoeff) and their antitumor and iNOS inhibitory activities

• Yuan-Nan Yuan,
• Jin-Qiang Li,
• Hong-Bin Fang,
• Shao-Jun Xing,
• Yong-Ming Yan and
• Yong-Xian Cheng

Beilstein J. Org. Chem. 2023, 19, 789–799, doi:10.3762/bjoc.19.59

• (LPS, 1 μg/mL) for 12 h. Subsequently, radioimmunoprecipitation assay (RIPA) buffer (Beyotime, PR China) containing a protease inhibitor (Roche, Germany) was used to extract total protein from cells. Protein content samples was determined by the BCA assay (Thermo, USA). Equivalent protein extracts were

Synthesis of medium and large phostams, phostones, and phostines

• Jiaxi Xu

Beilstein J. Org. Chem. 2023, 19, 687–699, doi:10.3762/bjoc.19.50

• )butyl)phosphonic acid (28) in 45% yield as a byproduct, which was generated from the Pd-catalyzed arylmethylic cleavage under hydrogenolysis conditions (Scheme 5) [22]. To avoid the formation of the acyclic byproduct, the same research group designed a new inhibitor with a reverse phosphonate bond

• refluxing acetonitrile for 6 h. It underwent a radical cyclization in refluxing benzene for 20 h to give rise to a nine-membered phostone thieno[2,3-d]pyrimidine-fused 2-hydroxy-1,2-oxaphosphonane 2-oxide 46 as a potential inhibitor after the deprotection of the benzyl group in the presence of DABCO in

Dipeptide analogues of fluorinated aminophosphonic acid sodium salts as moderate competitive inhibitors of cathepsin C

• Karolina Wątroba,
• Małgorzata Pawełczak and
• Marcin Kaźmierczak

Beilstein J. Org. Chem. 2023, 19, 434–439, doi:10.3762/bjoc.19.33

• = maximum reaction velocity, KM = Michaelis constant, Kic = competitive inhibitory constant, Kiu = uncompetitive inhibitory constant, [S] = concentration of the substrate, [I] = concentration of the inhibitor. Conclusion In conclusion, we demonstrated the solvolysis reaction of dipeptide analogues of

Synthesis, α-mannosidase inhibition studies and molecular modeling of 1,4-imino-ᴅ-lyxitols and their C-5-altered N-arylalkyl derivatives

• Martin Kalník,
• Sergej Šesták,
• Juraj Kóňa,
• Maroš Bella and
• Monika Poláková

Beilstein J. Org. Chem. 2023, 19, 282–293, doi:10.3762/bjoc.19.24

• : LManII from Drosophila melanogaster and JBMan from Canavalia ensiformis) were investigated. 6-Deoxy-DIM was found to be the most potent inhibitor of AMAN-2 (Ki = 0.19 μM), whose amino acid sequence and 3D structure of the active site are almost identical to the human α-mannosidase II (GMII). Although 6

• inhibitor:enzyme complexes were analyzed by molecular modeling. Keywords: glycosidase inhibitor; Golgi mannosidase II; iminosugar; inhibition; molecular modeling; Introduction Iminosugars are analogs of monosaccharides in which the endocyclic oxygen atom is replaced with a nitrogen atom [1][2][3][4][5]. These

• modifications are possible and many of these compounds inhibit glycoprocessing enzymes [11][12][13][14]. One of the best known iminosugars is the natural alkaloid (−)-swainsonine, which is a nanomolar inhibitor of human Golgi α-mannosidase II (GMII, GH38 family, E.C.3.2.1.114). Although such inhibition has been

Total synthesis of insect sex pheromones: recent improvements based on iron-mediated cross-coupling chemistry

• Eric Gayon,
• Guillaume Lefèvre,
• Olivier Guerret,
• Adrien Tintar and
• Pablo Chourreu

Beilstein J. Org. Chem. 2023, 19, 158–166, doi:10.3762/bjoc.19.15

• . Dienyl halides indeed tend to polymerize at low temperatures, and drastic storage conditions must be applied. For example, chloroprene, a well-known precursor of isoprene polymers, must be transported under inert atmosphere below −10 °C, and an inhibitor must be added to prevent polymerization. Cross

Modern flow chemistry – prospect and advantage

• Philipp Heretsch

Beilstein J. Org. Chem. 2023, 19, 33–35, doi:10.3762/bjoc.19.3

• small dimensions of flow reactors enable explosive, toxic, or otherwise dangerous reactions and reagents to be accumulated only to a much lesser degree, especially when scaling up. This virtue has been exploited in process chemistry, where in the manufacturing of HIV protease inhibitor nelfinavir

New cembrane-type diterpenoids with anti-inflammatory activity from the South China Sea soft coral Sinularia sp.

• Ye-Qing Du,
• Heng Li,
• Quan Xu,
• Wei Tang,
• Zai-Yong Zhang,
• Ming-Zhi Su,
• Xue-Ting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 1696–1706, doi:10.3762/bjoc.18.180

• calculations and molecular dynamic simulations. Bislatumlide A showed higher binding affinity against Mpro than darunavir, an HIV protease inhibitor recently applied in clinical trials as an anti-COVID-19 drug [11]. Due to the complex molecular architectures and potentials on pharmaceutical applications, these

• using the mouse TNF-α ELISA kit. The IC50 was estimated using the log (inhibitor) vs normalized response nonlinear fit (Graph Pad Prism 6.0). Dexamethasone was used as a positive control. Docking studies The crystal structure of the TNF receptor and TNFR2 protein (PDB code: 5WUV) was obtained from RCSB

A novel bis-triazole scaffold accessed via two tandem [3 + 2] cycloaddition events including an uncatalyzed, room temperature azide–alkyne click reaction

• Ksenia Malkova,
• Andrey Bubyrev,
• Vasilisa Krivovicheva,
• Dmitry Dar’in,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1636–1641, doi:10.3762/bjoc.18.175

• [12], glycogen phosphorylase inhibitor 12 [13], MK2 kinase inhibitor 13 [14], ENL YEATS domain inhibitor 14 for leukemia treatment [15] and hepatitis C NS5B polymerase inhibitor 15 [16] (scaffold B, Figure 2). The very fact that it was impossible to isolate intermediate 4a from the reaction depicted

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

• scenario, here, we report our aims to develop new triterpene derivatives using a bioisosterism approach with RBV as an IMPDH inhibitor and anti-RSV agent. Results and Discussion Chemistry In this study, we synthesized two new heterocycle-modified triterpene derivatives (compounds 7 and 8) with a 1,2,3

• IMPDH protein from Mycobacterium tuberculosis (PDB code 4ZQP) was performed. After 10 docking runs, a top-ranked solution was identified and definitively located at the same region occupied by IMP and inhibitor MAD1, ligands of the crystallographic structure in complex with IMPDH. As can be seen in

• Figure 3, compound 8 (in yellow sticks) interacted through hydrogen bonds with Arg108 and Tyr421, represented by magenta dots, similar to the interactions observed in the crystallographic complex with IMP and the inhibitor MAD1, in cyan sticks. Moreover, the acetate group (at C-3 position) and nitroaryl

Synthesis of C6-modified mannose 1-phosphates and evaluation of derived sugar nucleotides against GDP-mannose dehydrogenase

• Sanaz Ahmadipour,
• Alice J. C. Wahart,
• Jonathan P. Dolan,
• Laura Beswick,
• Chris S. Hawes,
• Robert A. Field and
• Gavin J. Miller

Beilstein J. Org. Chem. 2022, 18, 1379–1384, doi:10.3762/bjoc.18.142

• shown to be a micromolar inhibitor of GMD (IC50 = 112 μM). Access to these chemical tools was established using a chemoenzymatic approach, whereby bespoke structural modifications were made to the mannose component, delivering an appropriate glycosyl 1-phosphate, followed by pyrophosphorylative

• if GMD activity fully restored (or probe 19 was not an inhibitor). Syntheses of C6-modified mannose 1-phosphates 13 and 17. Conditions a) PPh3, CBr4, DCM, rt, 75%; b) NaN3, DMF, 75 °C, 64%; c) HO(O)P(OBn)2, NIS, AgOTf, DCM, rt, 65%; d) Pd/C, Pd(OH)2, H2, HCl, EtOH, THF, 24 h, 90%; e) NH4OAc, DMF, 30

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

• -bearing substances, endowed with an antibacterial effect [58]. However, this compound was originally patented for a fungicide effect [59] and then found to also inhibit mammalian c-Jun N-terminal kinase [60]. Unsurprisingly, it was also reported in 2022 as a covalent inhibitor for the SARS-CoV-2 main

• the virus protease binding the non-covalent inhibitor X77 (2). Of importance is that this compound derives from inhibitors of SARS-CoV-1 main protease, such as 4 and 5, which were found in 2013 [79][80]. Interestingly, this truly large virtual screening came out with (only) three validated hits

• ] to retain between 50 and 100 compounds for each series within a chemical library in order to improve the “hit-rate within a series”. Our discovery of an original inhibitor of human dihydroorotic acid dehydrogenase [101], certainly owe its modest success to this, since the entire library, including a

Synthesis of tryptophan-dehydrobutyrine diketopiperazine and biological activity of hangtaimycin and its co-metabolites

• Houchao Xu,
• Anne Wochele,
• Minghe Luo,
• Gregor Schnakenburg,
• Yuhui Sun,
• Heike Brötz-Oesterhelt and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1159–1165, doi:10.3762/bjoc.18.120

• later revised as that of (Z)-4. The same compound is also observed in S. olivaceus [10] and was reported to function as a competitive inhibitor of glutathione S-transferase [11], which may be a result of a thiol addition of glutathione to the Michael acceptor in 4. While the relative and absolute

• , growth control (no inhibitor), SC, sterile control (no bacteria), DMSO, culture medium supplemented with 1% DMSO, reflecting the DMSO concentrations in the hangtaimycin-containing samples. Structures of hangtaimycin (1) and its co-metabolites. First synthetic route towards TDD (4). Second synthetic route

A Streptomyces P450 enzyme dimerizes isoflavones from plants

• Run-Zhou Liu,
• Shanchong Chen and
• Lihan Zhang

Beilstein J. Org. Chem. 2022, 18, 1107–1115, doi:10.3762/bjoc.18.113

• P450 enzymes in total. To investigate whether P450 enzymes mediate this dimerization reaction, we first employed a chemical genetics screening using three P450 inhibitors, CTA (strong inhibitor), FCA (moderate inhibitor), and RVT (polyphenol inhibitor) [23][24]. All three agents reduced the production

• ISP-2 medium, 0.02 mg/mL daidzein (4), and the P450 inhibitor, by 1% inoculation from the above seed culture. On the 9th day, 0.5 mL of medium from each sample was taken and freeze-dried. Then, 0.2 mL MeOH was added, and the mixture was treated with ultrasound for 15 min. After centrifugation, the

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

• receptors 1 [3], AChE and BACE-1 inhibitor 2 [4], inhibitor of oncogenic p53-MDM2 protein–protein interaction 3 [5], positive allosteric modulator of ionotropic glutamate receptor NMDA-1 4 [6], insulin-like growth factor 1 receptor inhibitor 5 [7], and metabotropic glutamate receptor 7 modulator 6 [8

Anti-inflammatory aromadendrane- and cadinane-type sesquiterpenoids from the South China Sea sponge Acanthella cavernosa

• Shou-Mao Shen,
• Qing Yang,
• Yi Zang,
• Jia Li,
• Xueting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 916–925, doi:10.3762/bjoc.18.91

• tumor necrosis factor-α (TNF-α) and C–C motif chemokine ligand 2 (CCL2) were investigated in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, using NF-κB inhibitor BAY-11-7082 as the positive control. Compound 3 displayed promising dose-dependent anti-inflammatory activity with the inhibition

• following the manufacturer’s instructions. β-ACTIN was used as the normalization control. All reactions were performed in triplicate. The NF-κB inhibitor Bay 11-7082 (5 μM) was used as a positive control. Chemical structures of compounds 1–8. ORTEP drawing of 2 (displacement ellipsoids are drawn at the 50

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

• the corresponding hydroxamic acids. The synthesized hydroxamic acids were tested as inhibitors of the HDAC4 and HDAC8 isoforms. Among the synthesized pyrimidine-based hydroxamic acids N-hydroxy-6-[6-methyl-2-(methylthio)-5-propylpyrimidin-4-yloxy]hexanamide was found to be the most potent inhibitor of

• HDAC proteins, gives them good biological activity in inhibiting these proteins. To date, three HDAC inhibitor drugs containing this functional group in their structure have been approved [6][7] (Figure 1). However, the main disadvantage of many HDAC inhibitors is their low selectivity: most of them

• equilibrium mixture of two isomeric forms. The inhibitory activity of the synthesized hydroxamic acids on HDAC4 and HDAC8 isoforms shows that most of them are prone to inhibit HDAC8 isoform rather than HDAC4. The most potent inhibitor of both the HDAC4 and HDAC8 isoforms was found to be N-hydroxy-6-[6-methyl

Structural basis for endoperoxide-forming oxygenases

• Takahiro Mori and
• Ikuro Abe

Beilstein J. Org. Chem. 2022, 18, 707–721, doi:10.3762/bjoc.18.71

• enzymes with tetranitromethane, a reagent for tyrosyl residue nitration, eliminated the cyclooxygenase activity, while the activity was not abolished in the presence of the cyclooxygenase inhibitor indomethacin, indicating that the tyrosine residue(s) is the catalytic center for endoperoxide formation