Assembly of fully substituted triazolochromenes via a novel multicomponent reaction or mechanochemical synthesis

• Robby Vroemans,
• Yenthel Verhaegen,
• My Tran Thi Dieu and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 2689–2697, doi:10.3762/bjoc.14.246

• -known biologically active analogs (Scheme 5) [3]. Pd-catalyzed reactions were effected on bromotriazolochromene 5e. The piperazin-1-ylchromenes have been identified to be potent inhibitors at the 5-HT1A receptor and at the 5-HT transporter [45][46]. Thus, Buchwald–Hartwig amination of 1-phenylpiperazine

Non-native autoinducer analogs capable of modulating the SdiA quorum sensing receptor in Salmonella enterica serovar Typhimurium

• Matthew J. Styles and
• Helen E. Blackwell

Beilstein J. Org. Chem. 2018, 14, 2651–2664, doi:10.3762/bjoc.14.243

• against the EC90 of (enantiopure) L-OOHL (10 nM). Only 4 compounds (3% of the library) were able to inhibit SdiA activity in S. Typhimurium by greater than 65% under these conditions (Figure 2). This is a lower percentage of inhibitors than we typically identify for this AHL analog library, even with the

• compounds, R8 displayed the greatest inhibitory activity in SdiA – inhibition to 120% with an IC50 of 44 μM. Interestingly, similar compounds with shorter tail lengths are potent inhibitors in other receptors: R6, with a 9-carbon tail, is a potent inhibitor of QscR and LasR, and Q9, with an 8-carbon tail

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• coordinate population-wide group behaviours in the infection process like concerted secretion of virulence factors. One very important signalling network is the Pseudomonas quinolone signal (PQS) QS. With the aim to devise novel and innovative anti-infectives, inhibitors have been designed to address the

• network with compensatory mechanisms ensuring environmental adaptability and fine-tuned control of associated virulence genes (Figure 1). All four have been studied in the pursuit of quorum sensing inhibitors (QSI) to be used as blockers of P. aeruginosa pathogenicity [11][23]. Typically, a QS system of

• treatment. PqsA inhibitors Anthranilic acid analogues Since anthranilic acid (1) serves as a PqsA substrate, the first compound reported to inhibit PqsA is 6-FABA (2, Figure 3), which was able to block this enzyme and successfully suppressed the production of DHQ in PA14 strains at a rather high

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• potential (RIP), which is benchmarked with the reference methyl α-D-mannoside (1a) defined as RIP = 1, was increased up to 6900-fold [17]. The biphenyl mannosides (e.g., 4, 5) have subsequently been identified by the Ernst and Hultgren/Janetka groups as promising inhibitors of FimH-mediated bacterial

• that are interconnected by a hinge region. Interestingly, in vitro binding studies have been performed with the lectin domain only. Recent works suggested that the conformation of the two domains influence the protein’s affinity towards inhibitors and the biologically relevant state is a matter of

• , Titz et al. have developed small molecule LecB inhibitors derived from mannose and obtained potent monovalent inhibitors (compound 15) of LecB-mediated bacterial adhesion [47]. The sulfonamide 15 and cinnamide 16 were developed to take advantage of interactions with a nearby shallow pocket, and indeed

Synthesis of 3-aminocoumarin-N-benzylpyridinium conjugates with nanomolar inhibitory activity against acetylcholinesterase

• Nisachon Khunnawutmanotham,
• Cherdchai Laongthipparos,
• Patchreenart Saparpakorn,
• Nitirat Chimnoi and
• Supanna Techasakul

Beilstein J. Org. Chem. 2018, 14, 2545–2552, doi:10.3762/bjoc.14.231

• widely accepted hypothesis. AChE inhibition can increase ACh levels in the synaptic clefts and then alleviate the cognitive deficit in AD patients. The design of novel acetylcholinesterase inhibitors (AChEIs) has been mostly based on a dual-binding site strategy whereby the designed molecules

• well as with benzylpyridinium moieties [12][13][14] have been reported as dual-binding site AChE inhibitors. Recently we have reported the AChE inhibitory activity of the coumarin derivative, scopoletin conjugated with a pyridinium side chain (Figure 1) [15] and a docking study revealed that the

• scopoletin portion of the compound binds to amino acid residues in PAS, whereas the N-benzylpyridinium moiety binds to those present in the CAS of AChE. To develop potent AChE inhibitors, we were interested in aminocoumarin as a replacement of scopoletin due to the presence of the amino group in the former

Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives

• Nicholas G. Jentsch,
• Jared D. Hume,
• Emily B. Crull,
• Samer M. Beauti,
• Amy H. Pham,
• Julie A. Pigza,
• Jacques J. Kessl and
• Matthew G. Donahue

Beilstein J. Org. Chem. 2018, 14, 2529–2536, doi:10.3762/bjoc.14.229

• integration of viral DNA into host cell chromatin (Figure 1) [7][8][9]. In contrast to the FDA approved integrase strand transfer inhibitors (INSTIs) dolutegravir, elvitegravir, and raltegravir, arylquinolines 1 and 2 bind to a non-catalytic site of integrase (NCINI) via allosteric binding inhibition

• [C13H12BrNO3 + Na]+ 331.989277; found: 331.988788; anal. calcd for C13H12BrNO3: C, 39.70; H, 1.67; found C, 39.51; H, 1.74. Investigational non-catalytic HIV-1 Integrase inhibitors. Boehringer Ingelheim retrosynthesis of quinoline 1. Quinoline ring condensation strategies. Isatoic anhydrides from anthranilic

Synthesis of dihydroquinazolines from 2-aminobenzylamine: N³-aryl derivatives with electron-withdrawing groups

• Nadia Gruber,
• Jimena E. Díaz and
• Liliana R. Orelli

Beilstein J. Org. Chem. 2018, 14, 2510–2519, doi:10.3762/bjoc.14.227

• pharmacological interest. For example, vasicine is a 3,4-dihydroquinazoline alkaloid isolated from natural sources with antitumor activity [1]. Vasicine and deoxyvasicine are also potent butyrylcholinesterase (BChE) inhibitors [2]. Some synthetic derivatives containing the dihydroquinazoline scaffold have shown

• antimicrobial [3] and antifungal properties [4]. In addition, antiparasitic activity has been studied for some members of this family as inhibitors of trypanothione reductase [5], an essential enzyme of the kinetoplastid Trypanosoma brucei. Their activity as selective T-type calcium channel blockers [6][7][8][9

• ][10][11], as tumor suppressors [12] and as neuroprotective agents has also been reported [13]. Some related 2-amino-DHQs were studied as blood platelet aggregation inhibitors [14], antihypertensive agents [15] or inhibitors of β-secretase, an important target for Alzheimer’s disease [16]. Additionally

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

• Eszter Lajkó,
• Sarah Spring,
• Rózsa Hegedüs,
• Beáta Biri-Kovács,
• Sven Ingebrandt,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 2495–2509, doi:10.3762/bjoc.14.226

• Dau) had a synergistic effect with histone deacetylase inhibitors (e.g., prodrug of butyric acid) in several malignant cell lines [38]. This finding could also be a possible explanation for the increased cytotoxic effect of the conjugates containing acylated Lys compared to the parent one. Involvement

• could play a significant role in the antitumor activity of a drug-containing conjugate [40]. The association of PI3K activation with the antitumor activity of the conjugates was determined by pretreating the cells with PI3K inhibitors (wortmannin – W and LY294002 – LY). The antitumor effect of the

• conjugates and Dau on the cells pretreated with PI3K inhibitors or with DMSO (solvent of the inhibitors) was assessed by an alamarBlue-assay after 48 h of incubation. The results of the PI3K-assay were given by calculating the inhibition index as the ratio of the viability of the pretreated and control (DMSO

Synthesis of 1,4-imino-L-lyxitols modified at C-5 and their evaluation as inhibitors of GH38 α-mannosidases

• Maroš Bella,
• Sergej Šesták,
• Ján Moncoľ,
• Miroslav Koóš and
• Monika Poláková

Beilstein J. Org. Chem. 2018, 14, 2156–2162, doi:10.3762/bjoc.14.189

• target GMIIb enzyme. In contrast, no inhibition effect of the pyrrolidines against LManII was observed. The modification of the imino-L-lyxitol core is therefore a suitable motif for the design of inhibitors with desired selectivity against the target GMIIb enzyme. Keywords: azasugars; hydrolases

• ; inhibitors; pyrrolidines; synthesis; Introduction Carbohydrates as chiral templates for a construction of bioactive compounds are of steady interest in medicinal chemistry [1][2][3]. The polyfunctional nature of carbohydrate units offers many possibilities for the design of a wide variety of new compounds

• progress of tumor growth and metastasis. However, all potent GMII inhibitors, including swainsonine, showed also an undesired co-inhibition of lysosomal α-mannosidase (LM) that limits their use as therapeutic agents [25]. Since the discovery of swainsonine, new inhibitors of GMII that are based on its

Synthesis of 9-arylalkynyl- and 9-aryl-substituted benzo[b]quinolizinium derivatives by Palladium-mediated cross-coupling reactions

• Siva Sankar Murthy Bandaru,
• Darinka Dzubiel,
• Heiko Ihmels,
• Mohebodin Karbasiyoun,
• Mohamed M. A. Mahmoud and
• Carola Schulzke

Beilstein J. Org. Chem. 2018, 14, 1871–1884, doi:10.3762/bjoc.14.161

• topoisomerase inhibitors [5]. More recently, much interest in this research area is focused on the non-canonical quadruplex DNA (G4-DNA) [6][7][8]. Mostly based on the principles and requirements of ligands that bind to duplex DNA, numerous G4-DNA ligands have been developed to study their selectivity and

Synthesis of pyrimido[1,6-a]quinoxalines via intermolecular trapping of thermally generated acyl(quinoxalin-2-yl)ketenes by Schiff bases

• Svetlana O. Kasatkina,
• Ekaterina E. Stepanova,
• Maksim V. Dmitriev,
• Ivan G. Mokrushin and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2018, 14, 1734–1742, doi:10.3762/bjoc.14.147

• (quinoxaline fused by a six-membered heterocycle at the [a]-side) are promising biologically active compounds. Recent research studies revealed that they can act as inhibitors of poly(ADP-ribose) polymerase (PARP) [3], inhibitors of hepatitis C virus [4], 5-HT2C agonists [5][6][7], substances for controlling

β-Hydroxy sulfides and their syntheses

• Mokgethwa B. Marakalala,
• Edwin M. Mmutlane and
• Henok H. Kinfe

Beilstein J. Org. Chem. 2018, 14, 1668–1692, doi:10.3762/bjoc.14.143

• ) origin as potential therapeutic agents is also well documented. For instance, Luly et al. synthesized β-hydroxy sulfides coupled to leucine-valine (Leu-Val) replacements as inhibitors of human renin in order to lower blood pressure [100][101]. The high activity of these compounds is attributed to the

• presence of the hydroxy functional group acting as a transition-state analog. The synthesis of the inhibitors commenced with the conversion of aldehyde 127 into alkene 128 via a Wittig reaction followed by epoxidation to furnish epoxide 129. Regioselective opening of the epoxide ring with a thiolate gave

• the N-Boc protected β-hydroxy sulfide 130 as a key intermediate. Deprotection of the Boc followed by the imidation of the free amine with protected dipeptides that mimic Leu-Val produced the inhibitors of human renin 131 as depicted in Scheme 44. Yoshioka and co-workers reported two synthetic routes

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• -protected reducing glucose derivative 2 gave the β-glucoside 76 with good stereoselectivity, and the respective mannose derivative 24 resulted in the pure α-mannoside 77 in good yield (Scheme 12) [56]. In a general approach to coumarin-derived inhibitors of gyrase B, a group working at Hoechst Marion

• implemented in the preparation of novobiocin analogues [65], and formed a key step in the synthesis of new glycosidic PDE4 (phosphodiesterase type 4) inhibitors [66]. Also calix[4]arenes could be selectively mono- or diglycosylated by means of the Mitsunobu methodology [67][68]. The Mitsunobu reaction was

• -dialkoxycarbonylhydrazines [84]. This anomeric N-phthalimidation was later implemented by Nishimura et al. for the iminosugar 114 with phthalimide to give 115 in a high yield, en route to a new family of α-L-fucosidase inhibitors (Scheme 21) [85]. More generally, the preparation of modified glycosylamines under Mitsunobu

Lanyamycin, a macrolide antibiotic from Sorangium cellulosum, strain Soce 481 (Myxobacteria)

• Lucky S. Mulwa,
• Rolf Jansen,
• Dimas F. Praditya,
• Kathrin I. Mohr,
• Patrick W. Okanya,
• Joachim Wink,
• Eike Steinmann and
• Marc Stadler

Beilstein J. Org. Chem. 2018, 14, 1554–1562, doi:10.3762/bjoc.14.132

• masked as a hemiketal in bafilomycins, e.g., in bafilomycin A1 [11][12][13][14]. Bafilomycins are a family of macrolide antibiotics isolated from actinobacteria such as Micromonospora and Streptomyces species [11]. They are specific inhibitors of vacuolar ATPase (V-ATPase) [15]. The most studied compound

• of this class, bafilomycin A1 (Figure 3) is a useful biochemical tool as it prevents the re-acidification of synaptic vesicles once they have undergone exocytosis [14]. Bafilomycins are also known to be cytotoxic, inhibitors of autophagy, active against Gram-positive bacteria, yeast and fungi

• . The inoculum was removed 4 hours later and monolayers were washed three times with PBS and overlaid with fresh medium containing no inhibitors. Infected cells were lysed 3 days later, and reporter virus infection was determined by renilla luciferase activity. The cell viability was measured by

[3 + 2]-Cycloaddition reaction of sydnones with alkynes

• Veronika Hladíková,
• Jiří Váňa and
• Jiří Hanusek

Beilstein J. Org. Chem. 2018, 14, 1317–1348, doi:10.3762/bjoc.14.113

• acids – potent xanthine oxidoreductase inhibitors [40] or even 3,4-unsubstituted pyrazoles [16]. Both pyrazole carboxylic groups can be also modified to hydrazides and oxazole rings [26] or a new condensed pyridazine ring [27]. Less reactive dipolarophiles such as dibenzoylacetylenes (1,4-diphenylbut-2

Novel unit B cryptophycin analogues as payloads for targeted therapy

• Eduard Figueras,
• Adina Borbély,
• Mohamed Ismail,
• Marcel Frese and
• Norbert Sewald

Beilstein J. Org. Chem. 2018, 14, 1281–1286, doi:10.3762/bjoc.14.109

• glycol spacer with a terminal azide results in a complete loss of activity. Docking studies of the novel cryptophycin analogues to β-tubulin provided a rationale for the observed cytotoxicities. Keywords: cryptophycin; cytotoxic agents; novel payloads; tubulin inhibitors; tumour targeting; Introduction

• the other derivatives 23 and 24 (Figure 4). Besides hydrogen bond formation and binding affinity of inhibitors 2, 23 and 24, π-interactions and hydrophobic contacts with the binding pocket of the vinca domain were detected that would in turn increase the affinity of the inhibitor and its effect on the

A selective removal of the secondary hydroxy group from ortho-dithioacetal-substituted diarylmethanols

• Anna Czarnecka,
• Emilia Kowalska,
• Agnieszka Bodzioch,
• Joanna Skalik,
• Marek Koprowski,
• Krzysztof Owsianik and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2018, 14, 1229–1237, doi:10.3762/bjoc.14.105

• ] or vasodilating activities (II) [6]. Other ones have been reported as inhibitors of HIV-1 integrase and viral replication in cells [7] or antitubercular agents (III) [8][9]. Various diarylmethane-based molecules, like tolterodine (IV) [10], podophyllotoxin (V) [11] and lasofoxifene (VI) [12] have

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• programs due to their ability to act as gene expression inhibitors [5]. The recognition of DNA is both shape and sequence dependent as DNA polymorphism leads to significant changes in the groove structure. DNA is broadly categorized to possess three major forms: A, B and Z which differ from one another in

• as inhibitors of Werner and Bloom syndrome helicases and dual topoisomerase I/II inhibitors [37][38]. In order to improve DNA binding affinity and sequence specificity with reduced side effects, a series of synthetic hybrid molecules derived from distamycin and netropsin was synthesized and their

The first Pd-catalyzed Buchwald–Hartwig aminations at C-2 or C-4 in the estrone series

• Ildikó Bacsa,
• Dávid Szemerédi,
• János Wölfling,
• Gyula Schneider,
• Lilla Fekete and
• Erzsébet Mernyák

Beilstein J. Org. Chem. 2018, 14, 998–1003, doi:10.3762/bjoc.14.85

• -aminated estrone derivatives are described as inhibitors of estrogen biosynthesis. They are often synthesized via a three-step method including nitration, reduction, and functionalization of the amino group [1][2]. This three-step protocol may be simplified to involve only one or two steps by the

• -estrone 3-methyl ethers are also effective inhibitors [19]. Recently, we carried out the Pd-catalyzed C–C coupling of 2- and 4-iodo-13α-estrones as well as their 3-methyl ethers with p-substituted phenylacetylenes as terminal alkyne partners under microwave irradiation [20]. The regioisomerism markedly

• derivatives 6 and 11 without the need of changing the reaction conditions established for couplings at C-2. In continuation of our earlier work concerning the synthesis of 2-substituted 3-hydroxy-13α-estrone derivatives as potential enzyme inhibitors [20], here we were interested in the synthesis of 2-amino

Mechanochemistry of nucleosides, nucleotides and related materials

• Olga Eguaogie,
• Joseph S. Vyle,
• Patrick F. Conlon,
• Manuela A. Gîlea and
• Yipei Liang

Beilstein J. Org. Chem. 2018, 14, 955–970, doi:10.3762/bjoc.14.81

• ) and adenosine diphosphate ribose (ADPR) was also described. Subsequently, this methodology was applied to the preparation of a library of six ADPR carbonate derivatives in 23–68% yields (e.g., Scheme 14) and tested as sirtuin inhibitors [54]. The efficiency of phosphate coupling under mechanochemical

Volatiles from three genome sequenced fungi from the genus Aspergillus

• Jeroen S. Dickschat,
• Ersin Celik and
• Nelson L. Brock

Beilstein J. Org. Chem. 2018, 14, 900–910, doi:10.3762/bjoc.14.77

• the penny bun (Boletus edulis) [7], but can also inhibit the growth of other fungi [8] which likely contributes to the induction of systemic resistance in plants by Trichoderma [9]. Fungal volatiles can also act as self-inhibitors of fungal germination [10] or as attractants for insects involved in

Synthesis and stability of strongly acidic benzamide derivatives

• Frederik Diness,
• Niels J. Bjerrum and
• Mikael Begtrup

Beilstein J. Org. Chem. 2018, 14, 523–530, doi:10.3762/bjoc.14.38

• inhibitors (Figure 2) [15][16][17][18]. The reported derivatives all displayed activity, but only with similar or reduced potency compared to the corresponding benzoic acid derivatives. Application of deprotonated N-triflylbenzamide derivatives as counter anions in supramolecular crown ether compounds for

Carbohydrate inhibitors of cholera toxin

• Vajinder Kumar and
• W. Bruce Turnbull

Beilstein J. Org. Chem. 2018, 14, 484–498, doi:10.3762/bjoc.14.34

• released by Vibrio cholera in the host’s intestine. The toxin enters intestinal epithelial cells after binding to specific carbohydrates on the cell surface. Over recent years, considerable effort has been invested in developing inhibitors of toxin adhesion that mimic the carbohydrate ligand, with

• particular emphasis on exploiting the multivalency of the toxin to enhance activity. In this review we introduce the structural features of the toxin that have guided the design of diverse inhibitors and summarise recent developments in the field. Keywords: carbohydrate; cholera; multivalency; toxin

• of its B-subunits are different, but overall, an AB5 architecture is still preserved [11]. A detailed knowledge of the 3D structure of these toxins is informative for the design of effective inhibitors. Review Structure and function of cholera toxin Many crystallographic studies of the AB5 toxins

Recent developments in the asymmetric Reformatsky-type reaction

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 325–344, doi:10.3762/bjoc.14.21

• obtained in slightly lower yields (46–59% vs 52–62%) than the corresponding (R,S)-products 27d–g, as shown in Scheme 10. A related methodology was used by Levacher and Hardouin to develop a novel synthesis of primary chiral diamine 28, which is a common fragment to anti-apoptotic protein inhibitors, such

• reactions [27]. Synthesis of a common fragment to anti-apoptotic protein inhibitors through a Zn-mediated aza-Reformatsky reaction [28]. Synthesis of α,α-difluoro-β-(N-tert-butylsulfinyl)amino ketones through a Zn-mediated aza-Reformatsky reaction [29]. Synthesis of (2-oxoindolin-3-yl)amino esters through a

Novel amide-functionalized chloramphenicol base bifunctional organocatalysts for enantioselective alcoholysis of meso-cyclic anhydrides

• Lingjun Xu,
• Shuwen Han,
• Linjie Yan,
• Haifeng Wang,
• Haihui Peng and
• Fener Chen

Beilstein J. Org. Chem. 2018, 14, 309–317, doi:10.3762/bjoc.14.19

• pharmaceuticals, such as γ-aminobutyric acid (GABA) and γ-amino-β-hydroxybutyric acid (GABOB) analogues (baclofen HCl and pregabalin) [51][52][53][54], HMG-CoA reductase inhibitors (“statins”) [55][56][57], etc. The generality and scope of this methodology was further demonstrated in the alcoholysis of 8a with