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

• fragments in the structure of compound 5a) include compound 6 for the treatment of cognitive impairment [7], BET bromodomain inhibitors 7 [8] and 8 [9] for cancer treatment, σ1 receptor modulator 9 for diverse disorders [10] and bacterial regulatory RNA binder 10 [11] (scaffold A) as well as antidiuretic 11

A new route for the synthesis of 1-deazaguanine and 1-deazahypoxanthine

• Raphael Bereiter,
• Marco Oberlechner and
• Ronald Micura

Beilstein J. Org. Chem. 2022, 18, 1617–1624, doi:10.3762/bjoc.18.172

• ]-pyrimidines) [7][8][9] have been in the center of attention and were found to be effective compounds for the inhibition of various molecular targets associated with dysfunction of the central nervous system (e.g., as GABA and serotonin receptor modulators, or as inhibitors of phosphodiesterase PDE10A

One-pot double annulations to confer diastereoselective spirooxindolepyrrolothiazoles

• Juan Lu,
• Bin Yao,
• Desheng Zhan,
• Zhuo Sun,
• Yun Ji and
• Xiaofeng Zhang

Beilstein J. Org. Chem. 2022, 18, 1607–1616, doi:10.3762/bjoc.18.171

• nitrogen-based heterocycles, such as multicomponent reactions (MCRs) [18][19][20][21][22][23], one-pot cascade reactions [24][25][26][27][28][29][30][31][32] as good examples of PASE synthesis. We have reported a series of multicomponent reactions, like Groebke–Blackburn–Bienayme for making BET inhibitors

• UMB32 and UMB136 [33][34]. Zhang developed 4-aminoquinolines for the synthesis of fluorinated analogues of acetylcholinesterase (AChE) inhibitors [35] in cascade reactions, such as one-step syntheses of quinolines. Quinolin-4-ols involving histone acetyltransferases (HAT) inhibitors [36][37], as well as

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

• relied on a comparison of compound 8 with crystallographic ligands of IMPDH, on the basis that it would represent a secure interpretation of the site interactions similarity with inhibitors, thus, suggesting that this compound acts by the same mechanism. Therein, flexible docking for compound 8 to the

• ). One of the main known mechanisms of action of RBV is the depletion of intracellular GTP pools via the inhibition of cellular IMPDH induced by the 5-monophosphate metabolite of RBV [44]. Thus, our finding based on these results is that compound 8 may act similarly to IMPDH inhibitors and the active

• 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

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition

• Anaïs Rousseau,
• Guillaume Vincent and
• Cyrille Kouklovsky

Beilstein J. Org. Chem. 2022, 18, 1385–1395, doi:10.3762/bjoc.18.143

• . Common structural motifs include a polyunsaturated acyclic chain with an unsaturated lactone ring and an amine-containing side chain (Figure 1). These natural products have attracted much attention due to their original structure and to their activity as inhibitors of the serine/threonine phosphatase

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

• inhibitors to disrupt bacterial alginate production [3]. We recently disclosed the first series of targeted sugar nucleotide probes for GMD (Figure 1b) [4][5][6]. A C6-methyl analogue 6 was oxidised by GMD with direct evidence for a ketone product obtained. Most recently, C6-amide sugar nucleotide 7 was

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

• 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

• , including the 3-pyridyl bearing hydantoin 3. However, the same research group also performed a “fragment-guided virtual screening” using biological and structural data all based on the previously known inhibitors 4 and 5. As for the remarkable COVID Moonshot initiative, it is these 3-pyridyl- or

• benzotriazol-containing hits which were the crucial starting points to independently reach promising corona viruses main protease inhibitors such as compounds 6 and 7. And this was only achieved following many iterations of structure-based design, synthesis and assays of analogues [78][81][82]. Also of concern

Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates

• Péter Kisszékelyi,
• Tibor Peňaška,
• Klára Stankovianska,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 1195–1202, doi:10.3762/bjoc.18.124

• protease inhibitors. Given the potential usefulness of the benzothiazine scaffold as a biologically active unit and the peptidomimetic nature of many SARS-CoV-2 protease inhibitors [35], we decided to investigate the viability of attaching a 4H-benzo[b][1,4]thiazine-3-carboxylic core to amino acids

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

• Experimental section, 254 nm). b) Chemical genetics experiments indicated three P450 inhibitors could reduce the production of dimers derived from 4 (analytical method B to better analyze the isoflavone region, 254 nm). CTA: clotrimazole (2.5 µM), FCA: fluconazole (1000 µM), RVT: resveratrol (100 µM). CYP158C1

Scope of tetrazolo[1,5-a]quinoxalines in CuAAC reactions for the synthesis of triazoloquinoxalines, imidazoloquinoxalines, and rhenium complexes thereof

• Laura Holzhauer,
• Chloé Liagre,
• Olaf Fuhr,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2022, 18, 1088–1099, doi:10.3762/bjoc.18.111

• of a metal complex with an inverse triazoloquinoxaline ligand [12]. Imidazo[1,2-a]quinoxalines have been reported to possess anticancer and antitumor properties [27][28] and show activity as adenosine receptor antagonists [29] as well as PDE4 inhibitors [30]. The reaction of ring-fused tetrazoles to

Cathodic generation of reactive (phenylthio)difluoromethyl species and its reactions: mechanistic aspects and synthetic applications

• Sadanobu Iwase,
• Shinsuke Inagi and
• Toshio Fuchigami

Beilstein J. Org. Chem. 2022, 18, 872–880, doi:10.3762/bjoc.18.88

• )difluoromethyl group (ArSCF2) have potential biological applications such as anti-HIV-1 reverse transcriptase inhibitors and agrochemical applications [3][4]. Reurakul and Pohmakotr et al. carried out the reaction of PhSCF2Br with SmI2 in THF/iPrOH to generate PhSCF2 radicals followed by trapping with various

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

• to differently substituted pyrimidine rings via a methylene group bridge of varying length as potential HDAC inhibitors is described. The target compounds were obtained by alkylation of 2-(alkylthio)pyrimidin-4(3H)-ones with ethyl 2-bromoethanoate, ethyl 4-bromobutanoate, or methyl 6-bromohexanoate

• 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

• both the HDAC4 and HDAC8 isoforms, with an IC50 of 16.6 µM and 1.2 µM, respectively. Keywords: alkylation; aminolysis; HDAC inhibitors; hydroxamic acid; pyrimidine; Introduction Histone deacetylases (HDACs) are a family of intracellular proteins responsible for removing acetyl groups in histones

Synthesis of bis-spirocyclic derivatives of 3-azabicyclo[3.1.0]hexane via cyclopropene cycloadditions to the stable azomethine ylide derived from Ruhemann's purple

• Alexander S. Filatov,
• Olesya V. Khoroshilova,
• Anna G. Larina,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2022, 18, 769–780, doi:10.3762/bjoc.18.77

• found in natural compounds [9][10][11]. It is used in pharmaceuticals [12][13][14][15] and key intermediates [16][17]. Compounds containing a 3-azabicyclo[3.1.0]hexane moiety are antagonists of morphine-induced antinociception [18], histone deacetylase inhibitors [13], and opioid receptor antagonists

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

• are well conserved. While COX-1 is a constitutive enzyme present in most tissues, COX-2 is an isoenzyme induced in response to tumor promoters, growth factors, and cytokines [38][39][40]. Therefore, many COX-2 selective inhibitors are clinically used for treatments of inflammation, cancers, and pain

Shift of the reaction equilibrium at high pressure in the continuous synthesis of neuraminic acid

• Jannis A. Reich,
• Miriam Aßmann,
• Kristin Hölting,
• Paul Bubenheim,
• Jürgen Kuballa and
• Andreas Liese

Beilstein J. Org. Chem. 2022, 18, 567–579, doi:10.3762/bjoc.18.59

• stability investigations, it can be concluded that both selected enzyme preparations have adequate stability for the continuous application under high pressure. Kinetics Reaction kinetics were first measured for the immobilized epimerase. In the absence of inhibitors or backward reactions, the reaction rate

Chemistry of polyhalogenated nitrobutadienes, 17: Efficient synthesis of persubstituted chloroquinolinyl-1H-pyrazoles and evaluation of their antimalarial, anti-SARS-CoV-2, antibacterial, and cytotoxic activities

• Viktor A. Zapol’skii,
• Isabell Berneburg,
• Ursula Bilitewski,
• Melissa Dillenberger,
• Katja Becker,
• Stefan Jungwirth,
• Aditya Shekhar,
• Bastian Krueger and
• Dieter E. Kaufmann

Beilstein J. Org. Chem. 2022, 18, 524–532, doi:10.3762/bjoc.18.54

• pyrazole 7. A plausible mechanism for the formation of pyrazole 7. Synthesis of pyrazoles 9 and sulfoxide 10d. Synthesis of pyrazole 11. EC50 values of newly synthesized inhibitors on P. falciparum 3D7. Supporting Information Supporting Information File 152: Experimental procedures, characterization data

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

• commonly utilized as key intermediates for the synthesis of boron-containing peptidomimetics, which have been demonstrated to be efficient covalent ligands and valuable protease inhibitors endowed with various biological activities [5][6]. Going on with our interest in the synthesis of 3,3-disubstituted

Anomeric 1,2,3-triazole-linked sialic acid derivatives show selective inhibition towards a bacterial neuraminidase over a trypanosome trans-sialidase

• Peterson de Andrade,
• Sanaz Ahmadipour and
• Robert A. Field

Beilstein J. Org. Chem. 2022, 18, 208–216, doi:10.3762/bjoc.18.24

• natural substrate for sialidases and its chemical modification has been a useful approach to generate potent and selective inhibitors. Aiming at advancing the discovery of selective Trypanosoma cruzi trans-sialidase (TcTS) inhibitors, we have synthesised a small series of anomeric 1,2,3-triazole-linked

• differentiate both enzymes. Moreover, such selectivity might be reasoned based on a possible steric hindrance caused by a bulky hydrophobic loop that sits over the TcTS active site and may prevent the hydrophobic inhibitors from binding. The present study is a step forward in exploiting subtle structural

• the development of potent and selective inhibitors can serve as the basis for new therapeutics [3]. Despite the low primary sequence similarity among human, viral and non-viral sialidases (bacterial and protozoa), they all share a similar catalytic domain with active site residues highly conserved

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• direct access to cyclopeptides related to naturally occurring histone deacetylase (HDAC) inhibitors Cyl-1 and Cyl-2. Late stage modifications on the unsaturated amino acid side chain allow the introduction of functionalities which might coordinate to metal ions in the active center of metalloproteins

• ]. Three of these enzyme classes (I, II, and IV) contain Zn2+ within the active site, and therefore these enzymes can be affected by typical Zn2+-binding HDAC inhibitors. In cellular systems, an acetylated lysine of a histone is entering the cavity of the active site and gets coordinated to Zn2

• +. Subsequent attack of water forms a tetrahedral intermediate which results in a cleavage of the acetylated lysine. Most HDAC inhibitors act as substrate mimics and contain a zinc-binding motif. They competitively interact with the HDACs to form stable intermediates and therewith block the active site. Many

Ready access to 7,8-dihydroindolo[2,3-d][1]benzazepine-6(5H)-one scaffold and analogues via early-stage Fischer ring-closure reaction

• Irina Kuznetcova,
• Felix Bacher,
• Daniel Vegh,
• Hsiang-Yu Chuang and
• Vladimir B. Arion

Beilstein J. Org. Chem. 2022, 18, 143–151, doi:10.3762/bjoc.18.15

• University of Technology in Bratislava, Radlinského 9, SK-81237 Bratislava, Slovak Republic Institute of Organic Chemistry of the University of Vienna, Währinger Strasse 38, 1090 Vienna, Austria 10.3762/bjoc.18.15 Abstract Paullone isomers are known as inhibitors of tubulin polymerase and cyclin dependent

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis

• Ruan Carlos B. Ribeiro,
• Patricia G. Ferreira,
• Amanda de A. Borges,
• Luana da S. M. Forezi,
• Fernando de Carvalho da Silva and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 53–69, doi:10.3762/bjoc.18.5

• synthesis of a series of amino-N-methylated compounds 36 and phenoxy-1,2-naphthoquinones 35 with a carbon skeleton similar to β-lapachone (11), which could modulate hCE1 activity. Studies have shown that amino-N-methylated-1,2-naphthoquinones 36 are more selective and potent inhibitors than phenoxy-1,2

Efficient N-arylation of 4-chloroquinazolines en route to novel 4-anilinoquinazolines as potential anticancer agents

• Rodolfo H. V. Nishimura,
• Thiago dos Santos,
• Valter E. Murie,
• Luciana C. Furtado,
• Leticia V. Costa-Lotufo and
• Giuliano C. Clososki

Beilstein J. Org. Chem. 2021, 17, 2968–2975, doi:10.3762/bjoc.17.206

• malignant tumors, including platelet-derived growth factor receptor beta (PDGFR-β), vessel epidermal growth factor receptor (VEGFR-2), and epidermal growth factor receptor (EGFR) [5][6]. In addition, these compounds may act as vascular disrupting agents and tubulin polymerization inhibitors, contributing to

• apoptosis [7]. Figure 1 highlights the structures of three EGFR inhibitors approved by the United States Food and Drug Administration (FDA) and one known tubulin inhibitor: erlotinib (1), gefitinib (2), lapatinib (3), and MPC-6827 – verubulin (4) [5][7]. Given that 4-anilinoquinazolines are potential

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• reaction proceeds via a radical mechanism (path iii) [77], although use of radical inhibitors had little impact on the success of the reaction. It seems unlikely a radical pathway is involved in the reaction mechanism; however, it cannot be categorically excluded. In 2021, the Koh group demonstrated the

The PIFA-initiated oxidative cyclization of 2-(3-butenyl)quinazolin-4(3H)-ones – an efficient approach to 1-(hydroxymethyl)-2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-ones

• Alla I. Vaskevych,
• Nataliia O. Savinchuk,
• Ruslan I. Vaskevych,
• Eduard B. Rusanov,
• Oleksandr O. Grygorenko and
• Mykhailo V. Vovk

Beilstein J. Org. Chem. 2021, 17, 2787–2794, doi:10.3762/bjoc.17.189

• anti-inflammatory [9], antibacterial [10], antiarrythmic [11] activity; some representatives are CNS suppressors and poly-ADP ribose polymerase (PARP) inhibitors [12] (see Figure 1). Several approaches to obtain 2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-one derivatives of type 1 are known in the

Highly stereocontrolled total synthesis of racemic codonopsinol B through isoxazolidine-4,5-diol vinylation

• Lukáš Ďurina,
• Anna Ďurinová,
• František Trejtnar,
• Ľuboš Janotka,
• Lucia Messingerová,
• Jana Doháňošová,
• Ján Moncol and
• Róbert Fischer

Beilstein J. Org. Chem. 2021, 17, 2781–2786, doi:10.3762/bjoc.17.188

• naturally occurring (−)-codonopsinol B (1) and its N-nor-methyl analogue 2 were found to be effective α-glucosidase inhibitors, their racemic forms showed no evident antiproliferative activities against the selected human cancer cell lines U87-MG, HepG2, JEG-3 and MOLM-13 as well as immortalized proximal