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

Synthesis of 5-unsubstituted dihydropyrimidinone-4-carboxylates from deep eutectic mixtures

• Sangram Gore,
• Sundarababu Baskaran and
• Burkhard König

Beilstein J. Org. Chem. 2022, 18, 331–336, doi:10.3762/bjoc.18.37

• raltegravir, the first HIV-integrase inhibitor approved by the FDA for the treatment of HIV infection, derived from 5,6-dihydroxypyrimidine-4-carboxamide and N-methyl-4-hydroxypyrimidinone-carboxamide [18] and hydroxypyrimidinone carboxamide derivative P01, a potent inhibitor of Mycobacterium tuberculosis

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

• acid from the human host glycoconjugates onto its surface mucins to generate α-2,3-linked sialylated β-galactopyranose units, thus contributing directly to the parasite adhesion and invasion of host cells [12]. Although TcTS is the major parasite virulence factor [13], there is no nanomolar inhibitor

• , it is known that PLP is a TcTS weak inhibitor [35][38] and its inhibition does not involve formation of a Schiff-base intermediate [38]. However, an allosteric modulation of neuraminidase activity has been attributed to a selective modification of murine respirovirus neuraminidase via specific PLP

• -Lysine binding [39]. Although PLP is not a reported neuraminidase inhibitor, its main interaction in the active site could be reasoned based on previous results with sialic acid-derived phosphonate analogues. In this regard, it has been suggested that the inhibition of different strains of influenza

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

• , such as histone deacetylases. Keywords: chelated enolate; Claisen rearrangement; HDAC inhibitor; peptide; late stage modification; Introduction Among natural products, peptidic structures have entered the limelight due to their extraordinary biological activities [1]. Often found as secondary

• B (Figure 1) is a cyclic tetrapeptide with a rather unusual epoxyketone side chain and was found to be a strong inhibitor of histone deacetylases (HDACs) [4][5]. HDACs are nuclear isozymes that regulate gene transcription via a dynamic process of acetylation and deacetylation of lysine residues of

• reactions. The chain length in 14 should generally be suitable for effective HDAC inhibition and the thioester moiety might act as a prodrug as described for the natural HDAC inhibitor largazole. Further investigations are currently in progress. Naturally occurring HDAC inhibitors. Naturally occurring HDAC

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

• unit is shifted and the indole ring is flipped (D). Isomer D has been shown to be a potent tubulin-polymerase inhibitor, while B was only mildly cytotoxic towards cancer cells at a concentration of 1 µM [5][6]. Backbone C, despite being very similar to the other three scaffolds, remained a synthetic

• challenge and practical synthesis is still missing in the literature. Its accessibility may enrich the arsenal of available tools for enzyme inhibitor design by increasing the number of hydrogen bonding donor and acceptor groups at the same side of the backbone, which may result in a tight binding with

Regioselective synthesis of methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates as new amino acid-like building blocks

• Jolita Bruzgulienė,
• Greta Račkauskienė,
• Aurimas Bieliauskas,
• Vaida Milišiūnaitė,
• Miglė Dagilienė,
• Gita Matulevičiūtė,
• Vytas Martynaitis,
• Sonata Krikštolaitytė,
• Frank A. Sløk and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2022, 18, 102–109, doi:10.3762/bjoc.18.11

• peptide-like structure. Heterocyclic amino acids and related compounds have been used to prepare synthetic DNA-encoded compound libraries for the discovery of small molecule protein ligands [23][24][25]. Recently, a highly specific and potent p38α kinase inhibitor containing a 3-amino-1-phenyl-1H-pyrazole

Chemoselective N-acylation of indoles using thioesters as acyl source

• Tianri Du,
• Xiangmu Wei,
• Honghong Xu,
• Xin Zhang,
• Ruiru Fang,
• Zheng Yuan,
• Zhi Liang and
• Yahui Li

Beilstein J. Org. Chem. 2022, 18, 89–94, doi:10.3762/bjoc.18.9

• structural, chemical, and biological properties [1]. For example, indomethacin is a nonselective inhibitor of COX1 and COX2, which is used for treating fever, pain and swelling [2]. Indole analog L-768242 exhibits nanomolar potencies (Ki) with superior selectivity for the hCB2 receptor over the human central

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

• good yields from the reaction of β-NQS 18 with 2-amino-5-selenothiazoles, such as 33 and 34. The authors reported that most of the compounds tested had similar anti-inflammatory properties or greater activity than meloxicam (Scheme 8). β-Lapachone (11) is a potent reversible inhibitor of the liver

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• curve could not be obtained since it requires high inhibitor concentrations. In addition, the wild-type sequence aAxWt was also tested in the competitive FP assay (Kd = 1448 ± 204 nM) against its FITC-labelled analogue fAxWt, which had been determined in a direct assay (Kd = 1191 ± 182 nM). Finally, the

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

• 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

• ). The EGFR inhibitor drugs bearing the 4-anilinoquinazoline moiety did not show potent cytotoxic activity against T98G cells (21.3 µM for erlotinib, and 37.8 µM for gefitinib). However, the tubulin polymerization inhibitor (verubulin), which contains 4-anilinoquinazoline in its chemical structure, was

Selective sulfonylation and isonitrilation of para-quinone methides employing TosMIC as a source of sulfonyl group or isonitrile group

• Chuanhua Qu,
• Run Huang,
• Yong Li,
• Tong Liu,
• Yuan Chen and
• Guiting Song

Beilstein J. Org. Chem. 2021, 17, 2822–2831, doi:10.3762/bjoc.17.193

• of the radical inhibitor 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) was subjected to the model reaction system, however, the reaction was not inhibited (Scheme 6B). This result suggests that no radical pathway is involved in this transformation. Based on the above experiments, a proposed mechanism

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

• . Codonopsinol B, together with its N-nor-methyl analogue 2, proved to be a potent α-glucosidase inhibitor (Figure 1). The potency it showed is higher than that of the known natural alkaloids such as radicamines A and B [3][4], and codonopsinol [5]. In contrast, the unnatural enantiomers of 1 and radicamine A

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• diarylamines that exist as rapidly interconverting atropisomers, and a VEGFR inhibitor from Wyeth contains a potentially atropisomeric N-arylquinoid [95][96]. In 2020, Gustafson and co-workers reported the first chiral phosphoric acid-catalyzed atroposelective electrophilic halogenation of N-arylquinoids 95, a

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• ), which may be responsible for such differences [24]. Initial results point at a conventional mechanism of action. Therein, the investigation of the cellular metabolism predicts triphosphate formation of the compounds by phosphorylation, and the resulting nucleotide is a selective inhibitor of the HIV-1

Exfoliated black phosphorous-mediated CuAAC chemistry for organic and macromolecular synthesis under white LED and near-IR irradiation

• Azra Kocaarslan,
• Zafer Eroglu,
• Önder Metin and
• Yusuf Yagci

Beilstein J. Org. Chem. 2021, 17, 2477–2487, doi:10.3762/bjoc.17.164

• ’’-pentamethyldiethylenetriamine (PMDETA, Aldrich), sodium azide (NaN3, Panreac), copper(II) chloride (CuIICl2, Merck), black phosphorus, dimethyl sulfoxide (DMSO) was used as received. Propargyl acrylate (Sigma), styrene (Merck) were purified before by using a basic alumina column to remove the inhibitor and then stored in the

(Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia

• Luiz Claudio Ferreira Pimentel,
• Lucas Villas Boas Hoelz,
• Henayle Fernandes Canzian,
• Frederico Silva Castelo Branco,
• Andressa Paula de Oliveira,
• Vinicius Rangel Campos,
• Floriano Paes Silva Júnior,
• Rafael Ferreira Dantas,
• Jackson Antônio Lamounier Camargos Resende,
• Anna Claudia Cunha,
• Nubia Boechat and
• Mônica Macedo Bastos

Beilstein J. Org. Chem. 2021, 17, 2260–2269, doi:10.3762/bjoc.17.144

• with the interactions found for IMT in the 3PYY crystal. The analysis of the inhibitor complexes 2c and 2g and BCR-Abl-1 showed interactions similar to those described for IMT (Figure 4a). Thus, compound 2c presented hydrogen-bonding interactions with Asp400 and Leu383 (hydrogen bonding energy of −1.31

• (Molecular Devices). After the first reading, the plate was returned to the incubator, and after one hour, the second reading was performed, completing the 48 hours of incubation with the compounds. The reference inhibitor used was IMT at fixed concentrations of 1 μM and 10 μM. Molecular docking The Molegro

• with the lowest interaction energy were evaluated. The interactions between BCR-Abl-1 and each inhibitor were analyzed using the ligand map algorithm, a standard algorithm in the MVD program [50]. The usual threshold values for H-bonds and steric interactions were used. All figures for molecular

Catalyzed and uncatalyzed procedures for the syntheses of isomeric covalent multi-indolyl hetero non-metallides: an account

• Ranadeep Talukdar

Beilstein J. Org. Chem. 2021, 17, 2102–2122, doi:10.3762/bjoc.17.137

• -hydrogen in the diallylsulfoxide (123) did not allow any Pummerer rearrangement [88][89]. Selenides In 1997, Showalter synthesized bis(indol-2-yl)selanes (or selenides) 130 having potential tyrosine kinase inhibitor activities [90][91]. The synthesis was achieved by reacting diselenium dichloride with (R