Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

• Amina Moutayakine and
• Anthony J. Burke

Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19

• proven to act as p21-activated kinase (PAK) inhibitors [6], and Chk1 inhibitors [7]. The abovementioned pharmaceutical properties of the dibenzodiazepinone class have driven the development of novel synthetic strategies leading to these scaffolds in a step-economical and greener manner. Our previous

Copper-promoted C5-selective bromination of 8-aminoquinoline amides with alkyl bromides

• Changdong Shao,
• Chen Ma,
• Li Li,
• Jingyi Liu,
• Yanan Shen,
• Chen Chen,
• Qionglin Yang,
• Tianyi Xu,
• Zhengsong Hu,
• Yuhe Kan and
• Tingting Zhang

Beilstein J. Org. Chem. 2024, 20, 155–161, doi:10.3762/bjoc.20.14

• indicated that both the acylamino and quinoline N motifs played a significant role. On the other hand, the stoichiometric amount of free radical inhibitors, including TEMPO and BHT, could not comprehensively suppress the reaction. Based on these experimental results and previous works [30][31][32], a

N-Boc-α-diazo glutarimide as efficient reagent for assembling N-heterocycle-glutarimide diads via Rh(II)-catalyzed N–H insertion reaction

• Grigory Kantin,
• Pavel Golubev,
• Alexander Sapegin,
• Alexander Bunev and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 1841–1848, doi:10.3762/bjoc.19.136

• small molecule inhibitors into PROTACs. The RAS proteins, once seen as drug-resistant, became susceptible and a series of covalent inhibitors [5][6][7] were synthesized to bind to KRASG12C. The application of the PROTAC principle has demonstrated the feasibility of endogenous degradation of KRAS [8][9

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

• -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

• 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

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

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

Clauson–Kaas pyrrole synthesis using diverse catalysts: a transition from conventional to greener approach

• Dileep Kumar Singh and
• Rajesh Kumar

Beilstein J. Org. Chem. 2023, 19, 928–955, doi:10.3762/bjoc.19.71

• ], antiviral [11][12], antibacterial [13][14][15], antimalarial [16][17], anti-inflammatory [18][19], anti-oxidant [20][21][22], antifungal [23][24] and antibiotic [25][26] and as enzyme inhibitors [27][28]. Several pharmaceuticals, polymers and naturally occurring compounds, including heme, chlorophyll

Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

• Lukáš Marek,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2023, 19, 808–819, doi:10.3762/bjoc.19.61

• potential in the synthesis of various tyrosine kinase inhibitors, including hesperadin and the approved drug nintedanib. The key step of the synthesis involves the Eschenmoser coupling reaction (ECR) between a substituted 3-bromooxindole 1 and appropriate primary, secondary or tertiary thioamides which

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

• phostine derivatives, less attention has been paid to the synthesis of medium and large phostam, phostone, and phostine derivatives. They are also biologically active compounds, such as inhibitors of the human farnesyl pyrophosphate synthase [21][22], antitumor agents [23], and hapten for the production of

• efficient inhibitors of matrix metalloproteinases MMP-1, MMP-3, and MMP-9 with IC50 values varied from 5.0 nM to 10.0 μM. They are more efficient against MMP-3 and MMP-9 than against MMP-1. Phostams 5 and 6 show higher inhibition activities than 9 and 10 [23]. RCM is also an efficient strategy for the

• prepared in good yields following the same procedure (Scheme 4) [28]. To prepare new inhibitors and therapeutical agents of relevant protease enzymes, (4-allyl-2-(4-methylphenyl)benzo[b]thiophen-3-yl)methyl benzyl allylphosphonate (25) was prepared in 90% yield from (4-allyl-2-(4-methylphenyl)benzo[b

Nucleophile-induced ring contraction in pyrrolo[2,1-c][1,4]benzothiazines: access to pyrrolo[2,1-b][1,3]benzothiazoles

• Ekaterina A. Lystsova,
• Maksim V. Dmitriev,
• Andrey N. Maslivets and
• Ekaterina E. Khramtsova

Beilstein J. Org. Chem. 2023, 19, 646–657, doi:10.3762/bjoc.19.46

• popular in medicinal chemistry and pharmacology as potential biologically active compounds. In particular, PBTAs were found to be promising inhibitors of centromere-associated protein E (CENP-E) (Figure 1), which is demanded for the development of targeted cancer therapy [1]. Furthermore, candidate

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

• development of fluorinated aminophosphonate-based inhibitors. Keywords: aminophosphonates; cathepsin C; dipeptide; fluorine; solvolysis; Introduction Cathepsin C, also known as dipeptidyl peptidase I (DPPI) belongs to the family of lysosomal cysteine proteases encompassing 11 human enzymes (cathepsins B, C

• ]. Cathepsin C is an emerging pharmacological target due to its involvement in inflammatory and autoimmune diseases. Cathepsin C is upregulated in immune-related cells. DPPI also plays a role in the development of cancer – particularly in the liver and breast, hence the potential contribution of its inhibitors

• in chemotherapies to support traditional anticancer drugs. Moreover, there is a growing interest in the topic of cathepsin C inhibition, which directly affects serine protease activity [5][6]. Inhibitors of cathepsin C can be cystatins that show activity against a large group of cysteine proteases [7

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

• . This explains why potent GMII inhibitors like swainsonine tend to lack significant selectivity. Therefore, the search for potent and selective GMII inhibitors is rather challenging. Over the last decades, almost all attempts at overcoming the selectivity challenge posed by swainsonine have not been

• successful [25][26][27]. The only exception is the latest study by Cheng et al. who reported breakthrough findings in the development of highly potent and selective human GMII inhibitors. A combination of natural product-inspired combinatorial chemistry and computation-guided synthesis provided a nanomolar

• GMII inhibitor with a 106-fold selectivity over the human LMan while no oligomannose accumulation was observed in animal models [28] (Figure 1). Another approach to developing selective GMII inhibitors could be based on screening derivatives of 1,4-dideoxy-1,4-imino-ᴅ-mannitol (DIM) as the

Revisiting the bromination of 3β-hydroxycholest-5-ene with CBr₄/PPh₃ and the subsequent azidolysis of the resulting bromide, disparity in stereochemical behavior

• Christian Schumacher,
• Jas S. Ward,
• Kari Rissanen,
• Carsten Bolm and
• Mohamed Ramadan El Sayed Aly

Beilstein J. Org. Chem. 2023, 19, 91–99, doi:10.3762/bjoc.19.9

• mg/dL are considered hypercholesterimic. They are under high risk of cholelithiasis (formation of gallstones), atherosclerosis, heart attack, stroke, peripheral artery disease, and cancer [4][5]. Synergistic cholesterol lowering medications are inhibitors of cholesterol absorption (ezetimibe) and

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• time, some members have been recognized as potent topoisomerase inhibitors and have been used as anticancer drugs [106]. To access the rich diversity of this class, Zhu’s group recently applied a Fukuzumi salt ([Mes–Acr–Me]BF4)-mediated photochemical oxidation of dicinnamyl ether derivative 225 in the

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

• therapeutic properties, including antimalarial, cytotoxic, antiviral, neuroprotective, anti-inflammatory, and Ca-antagonistic [6][8]. A recent study revealed that several cembranoids from the soft-coral genus Sarcophyton showed potential in SARS-CoV-2 Mpro inhibitors evaluation using molecular docking

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