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

• , 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

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

• reaction, synthesis of glycosylurea, dihydropyrimidinones, pyrimidopyrimidinediones, and functionalized indole derivatives in this novel and green reaction medium [34][35][36][37][38]. We have also developed an efficient method for the synthesis of trisubstituted hydantoin derivatives from β,γ-unsaturated

Facile regiodivergent synthesis of spiro pyrrole-substituted pseudothiohydantoins and thiohydantoins via reaction of [e]-fused 1H-pyrrole-2,3-diones with thiourea

• Aleksandr I. Kobelev,
• Nikita A. Tretyakov,
• Ekaterina E. Stepanova,
• Maksim V. Dmitriev,
• Michael Rubin and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2019, 15, 2864–2871, doi:10.3762/bjoc.15.280

• good yields, and the products were isolated without applying preparative chromatography methods. Keywords: diversity-oriented synthesis; hydantoin; nitrogen heterocycles; rearrangement; thiourea; Introduction Hydantoin (imidazolidine-2,4-dione) derivatives are omnipresent among biologically active

• compounds [1]. Many of them are commercially available drugs, for example, anticonvulsants phenytoin [2] and albutoin [3], the muscle relaxant dantrolene [4], or the nonsteroidal antiandrogen agent enzalutamide [5] (Figure 1). Despite this fact, hydantoin derivatives belong to a special group of scaffolds

• rearrangement (PTR, Scheme 1) [8][9][10][11], which is a special case of a quite poorly investigated iminothiolactone–thiolactam rearrangement [12][13][14][15][16]. This reaction offers attractive opportunities for the design of libraries of regioisomeric hydantoin-based compounds for drug discovery. Spiro

Efficient synthesis of 4-substituted-ortho-phthalaldehyde analogues: toward the emergence of new building blocks

• Clémence Moitessier,
• Ahmad Rifai,
• Pierre-Edouard Danjou,
• Isabelle Mallard and
• Francine Cazier-Dennin

Beilstein J. Org. Chem. 2019, 15, 721–726, doi:10.3762/bjoc.15.67

• as well for the preparation of hydantoin derivatives to treat anti-inflammatory disorders [16]. More recently, in a study of Cao et al. [17] 4-HO-OPA was synthesized, once again in a low yield (4%) in order to produce the cucurbit[n]uril core. As shown by literature, the poor efficiency of 4

Sequential Ugi reaction/base-induced ring closing/IAAC protocol toward triazolobenzodiazepine-fused diketopiperazines and hydantoins

• Robby Vroemans,
• Fante Bamba,
• Jonas Winters,
• Joice Thomas,
• Jeroen Jacobs,
• Luc Van Meervelt,
• Jubi John and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 626–633, doi:10.3762/bjoc.14.49

• ; hydantoin; intramolecular azide–alkyne cycloaddition; Ugi reaction; Introduction The versatile bioactivities of multiring-fused heterocyclic scaffolds continue to attract significant attention in developing new methods for their synthesis. A plethora of functionalized fused heterocycles can be easily

• the synthesis of hydantoin-fused triazolobenzodiazepines starting from the Ugi reaction of o-azidobenzaldehyde (1a), propargylamine (2a), trichloroacetic acid (9) and benzyl isocyanide (4a, Scheme 5). The Ugi adduct was subjected to base-induced ring closing with NaOEt in EtOH which furnished the

• hydantoin intermediates; which on subsequent neutralization–dilution–IAAC afforded the expected hydantoin-fused benzodiazepine derivative 10a in 45% overall yield. In a similar way the cyclohexyl and p-methoxyphenyl-substituted compounds 10b and 10c were obtained in 82% and 62% overall yield, respectively

Poly(ethylene glycol)s as grinding additives in the mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins

• Andrea Mascitti,
• Massimiliano Lupacchini,
• Ruben Guerra,
• Ilya Taydakov,
• Lucia Tonucci,
• Nicola d’Alessandro,
• Frederic Lamaty,
• Jean Martinez and
• Evelina Colacino

Beilstein J. Org. Chem. 2017, 13, 19–25, doi:10.3762/bjoc.13.3

• complementing similar strategies was already described to avoid the formation of symmetrical ureas in solution [13]. The preparation of the hydantoin 2a was also investigated using batches of solid PEGs (Mw = 2000 and 3400) in which PEGs with lower molecular weight (Mw = 200–400) were eliminated before use by a

A new paradigm for designing ring construction strategies for green organic synthesis: implications for the discovery of multicomponent reactions to build molecules containing a single ring

• John Andraos

Beilstein J. Org. Chem. 2016, 12, 2420–2442, doi:10.3762/bjoc.12.236

• dihydropyridine, hydantoin, imidazole, indole, isoquinoline, isoxazole, oxazole, 4H-pyran, pyrazine, pyridazine, pyridine, pyridinone, pyrimidine, pyrimidone, pyrrole, 3H-quinazolin-4-one, quinoline, 1H-quinolin-4-one, and thiophene. For heterocycles that are composed of a fused aromatic ring, such as

Stereoselective synthesis of fused tetrahydroquinazolines through one-pot double [3 + 2] dipolar cycloadditions followed by [5 + 1] annulation

• Xiaofeng Zhang,
• Kenny Pham,
• Shuai Liu,
• Marc Legris,
• Alex Muthengi,
• Jerry P. Jasinski and
• Wei Zhang

Beilstein J. Org. Chem. 2016, 12, 2204–2210, doi:10.3762/bjoc.12.211

• [12][13][14][15][16][17], our lab has introduced a series of synthetic methods for heterocyclic compounds I–VI bearing heterocyclic rings such as hydantoin, pyrrolidine, pyrrolidinedione, piperazinedione, and dihydrobenzodiazepinedione (Scheme 1) [4][18][19][20][21]. All these scaffolds were prepared

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• employing radiolabelled UDP-N-acetylglucosamine. Disubstituted analogues were not active at the concentrations tested, suggesting that one free amino group is vital for activity. Hydantoin-derived compounds 79 with C12H25 and 80 with PhCH2 as residues R at the hydantoin moiety gave the best results with

• inhibition of lipid II formation at 6.25 μg/mL, which is comparable to muraymycin C1. Good activity was also found for hydantoin derivative 77 with the 4-FC6H4 substituent, showing inhibition of lipid II formation at 25 μg/mL. The only N-alkylated derivative inhibiting in the same order of magnitude was 83

• with n-C11H23 substitution. However, activities of the other compounds within this group also coincided with the previous observation that lipophilic compounds were more active. Overall, the tested monosubstituted hydantoin derivatives confirmed the assumed correlation between inhibitory activities and

Mechanism, kinetics and selectivity of selenocyclization of 5-alkenylhydantoins: an experimental and computational study

• Biljana M. Šmit,
• Radoslav Z. Pavlović,
• Dejan A. Milenković and
• Zoran S. Marković

Beilstein J. Org. Chem. 2015, 11, 1865–1875, doi:10.3762/bjoc.11.200

• , State University of Novi Pazar, Vuka Karadžića bb, 36300 Novi Pazar, Serbia 10.3762/bjoc.11.200 Abstract The mechanism and selectivity of a bicyclic hydantoin formation by selenium-induced cyclization are investigated. The proposed mechanism involves the intermediates formed by an electrophilic

• do not arise from the hydantoin nucleus itself but from different substituents that have been attached to it. During the last decades, the effect of the structural modification on the biological activity of the hydantoin derivatives has been studied intensively [12]. Due to their various biological

• activities polycyclic hydantoins, especially spirohydantoins [13][14][15][16][17][18][19][20] and fused [21][22][23] bicyclic hydantoin derivatives, have recently attracted great interest in both organic and medicinal chemistry. In our previous work, we reported the experimental results on the

Regioselective synthesis of 7,8-dihydroimidazo[5,1-c][1,2,4]triazine-3,6(2H,4H)-dione derivatives: A new drug-like heterocyclic scaffold

• Nikolay T. Tzvetkov,
• Harald Euler and
• Christa E. Müller

Beilstein J. Org. Chem. 2012, 8, 1584–1593, doi:10.3762/bjoc.8.181

• effects. We therefore identified the 1,2,4-triazine-containing scaffolds IV and VIII as promising novel target structures (Scheme 1). Depending on the starting material used, e.g., hydantoin I, or pyrazolidine-3,5-dione V, respectively, either 7,8-dihydroimidazo[5,1-c][1,2,4]triazine-3,6-diones IV (route

• hydantoin derivatives 12–18. Alkylation reactions of hydantoins are well documented in the literature [14][15][16][17][18]. Depending on the alkylation reagents and reaction conditions, either N1- or N3-substituted hydantoins are accessible [14][15][16][17]. The details of the successfully conducted N3

• isolated after chromatographic purification (Table 2). In order to demonstrate the tractability of the successive N1,N3-alkylation of hydantoin 6 we applied a three-step synthetic route to obtain compound 19 [17]. N3-Unsubstituted, N1-substituted hydantoins were obtained by a three-step synthetic procedure

Aryl nitrile oxide cycloaddition reactions in the presence of pinacol boronic acid ester

• Sarah L. Harding,
• Sebastian M. Marcuccio and
• G. Paul Savage

Beilstein J. Org. Chem. 2012, 8, 606–612, doi:10.3762/bjoc.8.67

• trans geometry in the cycloadduct, which is consistent with the concerted nature of the 1,3-dipolar cycloaddition reaction. For the cycloaddition reaction with the hydantoin compound, 3-methyl-1-(2-tert-butylphenyl)-5-methyleneimidazol-2,4-dione (Table 1, entry j), only a single diastereomer was

• detected. We have previously observed that nitrile oxide cycloadditions to this hydantoin and related compounds can show facial selectivity based on atropisomerism around the N-aryl bond [38][44]. With benzonitrile oxide the facial selectivity was 30:1 favouring addition anti to the tert-butyl group

The Eschenmoser coupling reaction under continuous-flow conditions

• Sukhdeep Singh,
• J. Michael Köhler,
• Andreas Schober and
• G. Alexander Groß

Beilstein J. Org. Chem. 2011, 7, 1164–1172, doi:10.3762/bjoc.7.135

• the mercapto hydantoin derivative 2g underwent the two step reaction smoothly and yielded the desired product 4ag in good quantity. In case of the 1H-benzoimidazole-2-thiol (2h), the selective S-alkylation failed. The utilized alkylation conditions favor the bis-alkylation, and hence the S-alkylated

A novel high-yield synthesis of aminoacyl p-nitroanilines and aminoacyl 7-amino-4-methylcoumarins: Important synthons for the synthesis of chromogenic/fluorogenic protease substrates

• Xinghua Wu,
• Yu Chen,
• Herve Aloysius and
• Longqin Hu

Beilstein J. Org. Chem. 2011, 7, 1030–1035, doi:10.3762/bjoc.7.117

• condense with p-nitrophenyl isocyanate to form the Nα-protected aminoacyl-pNAs [14]. However, commercially available p-nitrophenyl isocyanate often contains impurities due to degradation during storage; these impurities must be removed before use. In addition, a significant amount of hydantoin by-product

• was found in the reaction mixture. Although the addition of DMAP improved the amidation yields, the formation of hydantoin by-product also increased [15]. A modified procedure using Curtius rearrangement with diphenyl phosphorazidate (DPPA) was reported to minimize the side reaction, affording

Synthesis of some novel hydrazono acyclic nucleoside analogues

• Mohammad N. Soltani Rad,
• Ali Khalafi-Nezhad and
• Somayeh Behrouz

Beilstein J. Org. Chem. 2010, 6, No. 49, doi:10.3762/bjoc.6.49

• derivatives were conducted according to Scheme 1. As shown in Scheme 1, condensation of imidazole, 2-phenylimidazole, hydantoin, benzimidazole and benzotriazole with 2-bromoacetophenone and 4′-methoxy-2-bromoacetophenone gave the key intermediates, ketones 1a–1g. Based on our literature survey, we recognized