Synthesis and antimycotic activity of new derivatives of imidazo[1,2-a]pyrimidines

• Dmitriy Yu. Vandyshev,
• Daria A. Mangusheva,
• Khidmet S. Shikhaliev,
• Kirill A. Scherbakov,
• Oleg N. Burov,
• Alexander D. Zagrebaev,
• Tatiana N. Khmelevskaya,
• Alexey S. Trenin and
• Fedor I. Zubkov

Beilstein J. Org. Chem. 2024, 20, 2806–2817, doi:10.3762/bjoc.20.236

• inhibitor conformation found by docking is energetically unfavorable and therefore the expected activity of compound 5e will be much lower than that of compounds 4a–e. Molecular docking data can therefore be used to infer the structure–activity relationship. The substituent on the C-5 atom of

• Figure 5A for compound 4e. The heterocyclic nitrogen is indeed orientated towards the haem iron, with an N–Fe distance of 2.8 Å, which is slightly higher than the distance of 2.1 Å in the crystal complex with the inhibitor voriconazole. The benzene substituent on the C-6 atom is located in a hydrophobic

• probable reaction path of the interaction was suggested. Based on the docking data, N-aryl(alkyl)-7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-5-carboxamides as (S)-isomers were shown to be potent inhibitors of CYP51. These results allow us to consider these compounds as potential CYP51 inhibitor

5th International Symposium on Synthesis and Catalysis (ISySyCat2023)

• Anthony J. Burke and
• Elisabete P. Carreiro

Beilstein J. Org. Chem. 2024, 20, 2704–2707, doi:10.3762/bjoc.20.227

• RdRp inhibitor, and their evaluation in an in vitro polymerase assay, targeting SARS-CoV-2 [17]. The synthesis of the new molecules involved three modifications of the HeE1-2Tyr inhibitor, which included changing the core structure from a benzothiazole to a benzoxazole unit and simplifying it to

Photoredox-catalyzed intramolecular nucleophilic amidation of alkenes with β-lactams

• Valentina Giraldi,
• Giandomenico Magagnano,
• Daria Giacomini,
• Pier Giorgio Cozzi and
• Andrea Gualandi

Beilstein J. Org. Chem. 2024, 20, 2461–2468, doi:10.3762/bjoc.20.210

• well known as a potent β-lactamase inhibitor [33][34]. It is produced by the filamentous bacterium Streptomyces clavuligerus, but in low yield. Various clavams 2–5 have been identified (Figure 2B), either through isolation as natural metabolites or obtained by synthetic methods [35][36][37][38][39][40

Hypervalent iodine-mediated cyclization of bishomoallylamides to prolinols

• Smaher E. Butt,
• Konrad Kepski,
• Jean-Marc Sotiropoulos and
• Wesley J. Moran

Beilstein J. Org. Chem. 2024, 20, 2455–2460, doi:10.3762/bjoc.20.209

• many organocatalysts [3][4][5], natural products (e.g., the potent α-glucosidase inhibitor (−)-codonopsinol B) [6][7], and pharmaceutical drug molecules such as saxagliptin and ramipril (Figure 1) [8]. Accordingly, the development of methods to access substituted prolines and pyrrolidines is an

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

• ring was isolated from Ulocladium botrytis [219] and Microsphaeropsis olivacea [167]. Its structure was unambiguously confirmed by NMR spectroscopy and by total syntheses [44][220]. Ulocladol is a tyrosine kinase (p56lck) inhibitor leading to a reduction of enzyme activity to 7% at 0.02 µg/µL) [219

• furthermore turned out to be an inhibitor of trypanothione reductase (IC50: 4.3 μM) giving rise to an activity against Trypanosoma and Leishmania sp. [225] and inhibited Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) (but not the human orthologue) with an IC50 value of 5.9 µM [227]. Altenusin

• especially active against the kinase pp60c-Src (IC50: 20 nM) [231]. Altenusin turned out to be an inhibitor of α-glucosidase and pancreatic lipase (IC50: 46.1, 21.5 µM, respectively) [238], and of neutral sphingomyelinase (nSMase) with an IC50 value of 28 µM (but not of aSMase) [230][239]. It inhibited tau

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• Supporting Information File 1). Next, we paid attention to testing the conditions we developed for the synthesis of the SO2-containing analogue 2r of potent anticancer drug enastron in gram scale (Scheme 3). Enastron is a novel dihydropyrimidine-based mitotic kinesin spindle protein KSP/Eg5 inhibitor [36

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• wide range of pharmacological activities, such as anti-inflammatory, anti-arrhythmic, antitumor, antifungal, antibacterial, and anti-HIV activities [7][8][9][10][11][12][13]. For example, two N1-substituted bioactive indazoles are found in Figure 1, danicopan (1), a complement factor D inhibitor for

• the treatment of paroxysmal nocturnal hemoglobinuria, and CPI-637 (2), an inhibitor of both cyclic-AMP response element binding protein (CBP) and adenoviral E1A binding protein [14][15][16]. The N2-substituted indazole analogs pazopanib (3), an FDA-approved tyrosine kinase inhibitor used for the

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• of recently approved drugs by the FDA [31]. Fezolinetant (an NK3 receptor antagonist) and quizartinib (FLT3 inhibitor) are just a couple of examples among the drugs reaching the market in the last year. As shown in Scheme 2, ethyl (bromozinc)acetate (1a) was synthesized in flow by pumping a solution

Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• activity and thus block cancer formation [2]. Alangiumkaloids A, an isoquinolinone alkaloid isolated from Alangium salviiforlium, was reported to exhibit cytotoxic activity against cancer cells [3]. In 2018, duvelisib, a dual inhibitor of phosphoinositide-3 kinases, was firstly approved by the FDA for the

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

• activities of this supramolecular complex (Scheme 5), with positive in vitro activities in 20S proteasome core particles isolated from rabbit erythrocytes [28]. The sulfonamide 30 (Scheme 6) has been evaluated as inhibitor of human carbonic anhydrase I/II (hCA I and II), which catalyze the reversible

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• search of new bioactive compounds, as evidenced by the fact that they are present in many marketed drugs [1][2]. These substructures are found fused with other heterocycles in many cases, as illustrated by the antineoplastic dibromophakellstatin [3][4][5][6], the CDK inhibitor trilaciclib [7] or the

• kinase inhibitor tinengotinib [8] (Figure 1). Despite the interest of these structures, several drawbacks are typically found during their syntheses, for instance the difficulty in obtaining certain functionalizations or the need of long, elaborated reaction sequences. In recent years, multicomponent

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• synthesized similarly and their evaluation as inhibitors of the same enzyme [41][42], many of which demonstrated activity comparable to the inhibitor RM-532-105 [43]. In 2018, Merino-Montiel and Montiel-Smith prepared spiro 1,3-oxazolidin-2-ones (spirocarbamates) and a series of spiro 2-substituted amino-4,5

• , the compounds demonstrated significant acetylcholinesterase inhibitory activity, with IC50 values ranging from 0.35 to 0.50 µM compared to the reference inhibitor tacrine (IC50 value = 0.29 µM). In 2016, El-Shahawi et al. presented the synthesis of novel spiro 1,3-thiazolidin-4-one derivatives at the

• as a 17β-HSD3 inhibitor [42]. The same research group reported a new family of 3-spiromorpholinones derived from ADT bearing hydrophobic substituents [43][62]. The synthetic key step involved a regioselective aminolysis of the oxirane 131 with different ʟ- or ᴅ-amino acids (53–99% yields) to obtain

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• a class I SAM-dependent MT. The closest structural homologues with defined biosynthetic pathways are CcbJ and KedS8. These enzymes N-methylate the antibiotic lincosamide celesticetin and the anticancer protein kedaricidin, respectively. Crocagin A is a potent inhibitor of the RNA binding protein

Rhodium-catalyzed homo-coupling reaction of aryl Grignard reagents and its application for the synthesis of an integrin inhibitor

• Kazuyuki Sato,
• Satoki Teranishi,
• Atsushi Sakaue,
• Yukiko Karuo,
• Atsushi Tarui,
• Kentaro Kawai,
• Hiroyuki Takeda,
• Tatsuo Kinashi and
• Masaaki Omote

Beilstein J. Org. Chem. 2024, 20, 1341–1347, doi:10.3762/bjoc.20.118

• heterocyclic or aliphatic bromides scarcely proceeded. A Rh(III)–bis(aryl) complex, which might be formed from RhCl(PPh3)3 and the aryl Grignard reagents, plays an important role in giving the homo-coupling products in this reaction. Furthermore, we applied the reaction to the synthesis of a novel inhibitor

• for integrins which is critical for several diseases. Keywords: biphenyltetracarboxylic acid; homo-coupling; integrin inhibitor; rhodium catalyst; Ullmann-type reaction; Introduction The Ullmann reaction is a coupling reaction of aryl halides using copper, traditionally using metallic copper-bronze

• developing novel inhibitors of integrin function, we identified a drug candidate (10n) through high throughput screening (HTS) that inhibits the integrin complex formation, which is an important step for integrin activation. The binding inhibitor 10n was effective as IC50 of 190 μM in AlphaScreen system, and

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

• Maksim V. Kvach,
• Stefan Harjes,
• Harikrishnan M. Kurup,
• Geoffrey B. Jameson,
• Elena Harjes and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2024, 20, 1088–1098, doi:10.3762/bjoc.20.96

• characterised as the most potent inhibitor of human CDA, but the quick degradation in water limited the applicability as a potential therapeutic. To improve stability in water, we synthesised derivatives of phosphapyrimidine nucleoside having a CH2 group instead of the N3 atom in the nucleobase. A charge

• development of more potent CDA and APOBEC3 inhibitors. Keywords: APOBEC3; cytidine deaminase; enzyme activity; inhibitor; nucleoside; nucleotide; zebularine; Introduction Spontaneous hydrolytic deamination of cytosine to uracil (Figure 1A) is very slow under ambient conditions [1], but it is greatly

• . Recently, a combination of the CDA inhibitor (4R)-2′-deoxy-2′,2′-difluoro-3,4,5,6-tetrahydrouridine (cedazuridine, Ib, Figure 1B) with the anticancer drug decitabine was approved as an oral pill (i.e., C-DEC or ASTX727) for the treatment of patients with intermediate or high-risk myelodysplastic syndrome

Mild and efficient synthesis and base-promoted rearrangement of novel isoxazolo[4,5-b]pyridines

• Vladislav V. Nikol’skiy,
• Mikhail E. Minyaev,
• Maxim A. Bastrakov and
• Alexey M. Starosotnikov

Beilstein J. Org. Chem. 2024, 20, 1069–1075, doi:10.3762/bjoc.20.94

• inhibitor of homeodomain-interacting protein kinases (HIPKs) [32], and combretastatin A-4 analogs evaluated for their anticancer properties against a panel of 60 human cancer cell lines [33] (Figure 2). The structures of all new compounds were confirmed by 1H and 13C NMR and HRMS. X-ray diffraction studies

Novel analogues of a nonnucleoside SARS-CoV-2 RdRp inhibitor as potential antivirotics

• Luca Julianna Tóth,
• Kateřina Krejčová,
• Milan Dejmek,
• Eva Žilecká,
• Blanka Klepetářová,
• Lenka Poštová Slavětínská,
• Evžen Bouřa and
• Radim Nencka

Beilstein J. Org. Chem. 2024, 20, 1029–1036, doi:10.3762/bjoc.20.91

• . One of the most targeted RNA viruses of the last years is, without doubt, SARS-CoV-2, the cause of the recent COVID-19 pandemic. HeE1-2Tyr, a known inhibitor of flaviviral RdRp, has been discovered to also have antiviral potency against this coronavirus. In this study, we report three distinct

• : antivirotics; nonnucleotide inhibitor; RNA-dependent RNA polymerase; SARS-CoV-2; Introduction Epidemics caused by various viral infections, such as AIDS, Zika fever, Dengue fever, or Ebola, are a constant threat to communities of all sizes [1]. The COVID-19 pandemic, caused by the newly emerged severe acute

• the polymerase, not only across the CoV group but also in other RNA viruses [13]. A great example of this phenomenon is remdesivir, which was originally developed as a therapeutic agent against Ebola virus [18][19]. HeE1-2Tyr (1) was originally identified by Tarantino et al. [20] as a potent inhibitor

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• tm-phen (0.7–2 mol %) for others, 14 indole derivatives were isolated with yields of up to 100%. Among the 14 examples is a more soluble derivative of a KDR kinase inhibitor identified by researchers from Merck for blocking tumor-induced angiogenesis [31] (Scheme 13). An interesting synthesis of 3

Enantioselective synthesis of β-aryl-γ-lactam derivatives via Heck–Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles

• Arnaldo G. de Oliveira Jr.,
• Martí F. Wang,
• Rafaela C. Carmona,
• Danilo M. Lustosa,
• Sergei A. Gorbatov and
• Carlos R. D. Correia

Beilstein J. Org. Chem. 2024, 20, 940–949, doi:10.3762/bjoc.20.84

• followed by a sequential Jones oxidation. The overall method displays a broad scope and good enantioselectivity, favoring the (R) enantiomer. The applicability of the protocol is highlighted by the efficient enantioselective syntheses of the selective phosphodiesterase-4-inhibitor rolipram and the

• inhibitor (R)-rolipram (5b) [15], and the commercial drug (R)-baclofen hydrochloride (6), used to treat muscle spasticity from spinal cord injury and multiple sclerosis [16]. Results and Discussion Desymmetrization of N-protected 2,5-dihydro-1H-pyrroles Some initial results and reaction optimization Based

• Supporting Information File 1 for details). Given the presence of the 4-aryl-γ-lactam motif in the phosphodiesterase-4 inhibitor rolipram, and in a synthetic intermediate for the baclofen drug, the Heck products 4bg and 4bq were used as starting material for their syntheses. N-Tosylated lactams 4bg and 4bq

(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

• ]. The ability of 1,5-BCHeps to act as bioisosteres of meta-benzenes was also studied by Anderson and co-workers. They reported the comparison of fatty acid amide hydrolase inhibitor URB597 with its 1,5-BCHep isostere 146 (Figure 21) [27]. They found that while replacement of one of the meta-benzenes

Genome mining of labdane-related diterpenoids: Discovery of the two-enzyme pathway leading to (−)-sandaracopimaradiene in the fungus Arthrinium sacchari

• Fumito Sato,
• Terutaka Sonohara,
• Shunta Fujiki,
• Akihiro Sugawara,
• Yohei Morishita,
• Taro Ozaki and
• Teigo Asai

Beilstein J. Org. Chem. 2024, 20, 714–720, doi:10.3762/bjoc.20.65

• inhibitor aphidicolin [28] and a ribosome-targeting antibiotic pleuromutilin [29] (Figure 1), they remained as underexplored targets in genome-mining approaches. In this study, we examined the biosynthetic genes for LRDs and identified two TCs consisting of αβ and αβγ domains. Heterologous expression in

Production of non-natural 5-methylorsellinate-derived meroterpenoids in Aspergillus oryzae

• Jia Tang,
• Yixiang Zhang and
• Yudai Matsuda

Beilstein J. Org. Chem. 2024, 20, 638–644, doi:10.3762/bjoc.20.56

• secondary metabolites, filamentous fungi stand out as the most prolific producers of meroterpenoids [1][2][3]. Representative fungal meroterpenoids of medicinal importance include pyripyropene A, a cholesterol acyltransferase inhibitor [4]; fumagillin, an antimicrobial agent [5]; and mycophenolic acid, a

• strong inosine 5-monophosphate dehydrogenase inhibitor [6]. The biosynthesis of fungal meroterpenoids has garnered interest in the organic chemistry field due to their structural complexity and associated intriguing enzymatic reactions and has thus been extensively researched for over a decade, providing

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

• Alexander Yanovich,
• Anastasia Vepreva,
• Ksenia Malkova,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48

• antagonist 7 [33], and aldosterone synthase inhibitor 8 [34]) as well as natural products (e.g., new alkaloids deoxytryptoquivaline and deoxynortryptoquivaline from fungus Aspergillus clavatonanicus identified as natural cardiomyocyte-protective agents against cold ischemic injury [35] and possible natural

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

• binding affinity to enzyme targets, e.g., acyl-ACP thioesterases, belonging to the protein family of FATs, was demonstrated by using co-crystallization, fluorescence-based thermal shift assays, and chemoproteomics techniques [3]. Likewise, methiozolin (2) is a recently assigned FAT inhibitor that has

• lead structure with ample space for structural variations. By formally replacing one pyridine moiety of 1,8-naphthyridine 4 by a five-membered thiazole unit, we have identified thiazolo[4,5-b]pyridine 5 as a strong inhibitor of acyl-ACP thioesterase, which has further been confirmed via an X-ray co