The design and synthesis of an antibacterial phenothiazine–siderophore conjugate

• Abed Tarapdar,
• James K. S. Norris,
• Oliver Sampson,
• Galina Mukamolova and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2018, 14, 2646–2650, doi:10.3762/bjoc.14.242

• ]. Phenothiazines are a privileged scaffold in drug discovery most noted for their use as antipsychotic drugs including chlorpromazine, trifluoperazine, and thioridazine. However, such drugs have also long been noted for their significant antimicrobial activity particularly against Staphylococcus aureus and

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

• highlights the published drug discovery efforts providing insights into the compound binding modes if available. Furthermore, suitability of the individual targets for pathoblocker design is discussed. Keywords: anti-infectives; pathoblockers; PQS; Pseudomonas aeruginosa; quorum sensing; Introduction In

• the pqs system and 2-(2-hydroxyphenyl)thiazole-4-carbaldehyde used by the iqs system (Figure 1). Strategies addressing las and rhl have been reviewed elsewhere [5][11], while to date one study on iqs inhibition has been reported [23]. Many drug discovery efforts towards effective pathoblockers have

• into the focus [89]. Due to the complex nature of virulence phenotype assays as well as ADME/T testing cascades assembling the required teams, expertise, and resources might be a challenge especially for academic groups. Hence, often proclaimed drug discovery timelines for target-to-candidate projects

Synthesis of a leopolic acid-inspired tetramic acid with antimicrobial activity against multidrug-resistant bacteria

• Luce Mattio,
• Loana Musso,
• Leonardo Scaglioni,
• Andrea Pinto,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2018, 14, 2482–2487, doi:10.3762/bjoc.14.224

• , as they possess biologically validated structures, which could become suitable leads in drug discovery [2]. Recently, our research group reported the first total synthesis of leopolic acid A (Figure 1), a fungal metabolite from a terrestrial-derived Streptomyces sp. isolated from the rhizosphere of

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• how this protocol translates seamlessly to drug discovery in the LSF strategy. In a method that is complementary to their C–H amination strategy, Nicewicz et al. have reported the SNAr-type addition of nucleophiles to methoxybenzene derivatives at the ipso position, as opposed to the C–H amination

• nicotinamides to highly functionalised quinolines, such as the antimalarial drug quinine. The ability of this protocol to tolerate such highly functionalised molecules, with such a variety of functional groups present, really justifies the claims of the authors that this protocol is ideal for LSF in drug

• discovery programs. The scope of the alkyl chains is also tremendous, with primary, secondary and tertiary alkyl trifluoroborates being used. The team also addresses the availability of these substrates, showing how these can be easily made in one step from the corresponding alkyl bromides, using a method

Synthesis of new tricyclic 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepine derivatives by [3⁺ + 2]-cycloaddition/rearrangement reactions

• Lin-bo Luan,
• Zi-jie Song,
• Zhi-ming Li and
• Quan-rui Wang

Beilstein J. Org. Chem. 2018, 14, 1826–1833, doi:10.3762/bjoc.14.155

• present synthetic protocol paves the way for further applications in drug-discovery research. Examples of marketed pharmaceutical 1,2,4-triazolobenzodiazepines. Crystal structure of salt 10k. The displacement ellipsoids are drawn at the 30% probability level. Crystal structure of the free base 13e. The

Two new 2-alkylquinolones, inhibitory to the fish skin ulcer pathogen Tenacibaculum maritimum, produced by a rhizobacterium of the genus Burkholderia sp.

• Dandan Li,
• Naoya Oku,
• Atsumi Hasada,
• Masafumi Shimizu and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2018, 14, 1446–1451, doi:10.3762/bjoc.14.122

• Pseudomonas aeruginosa. A series of chemoecological studies of P. aeruginosa has uncovered multifunctional roles of this quinolone class as antibacterial, antifungal, iron-chelating, and autoinducer agents to assist the survival of the producing organisms [32]. Additionally, drug discovery attempts have

Synthesis of chiral 3-substituted 3-amino-2-oxindoles through enantioselective catalytic nucleophilic additions to isatin imines

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 1349–1369, doi:10.3762/bjoc.14.114

• advances, the involvement of other types of organocatalysts and metal ligands will have to be investigated in these transformations along with the use of other nucleophiles to even more extend the library of chiral 3-substituted 3-amino-2-oxindoles available for drug discovery. Mannich reaction of N-Boc

Stereoselective nucleophilic addition reactions to cyclic N-acyliminium ions using the indirect cation pool method: Elucidation of stereoselectivity by spectroscopic conformational analysis and DFT calculations

• Koichi Mitsudo,
• Junya Yamamoto,
• Tomoya Akagi,
• Atsuhiro Yamashita,
• Masahiro Haisa,
• Kazuki Yoshioka,
• Hiroki Mandai,
• Koji Ueoka,
• Christian Hempel,
• Jun-ichi Yoshida and
• Seiji Suga

Beilstein J. Org. Chem. 2018, 14, 1192–1202, doi:10.3762/bjoc.14.100

• physiological and pharmacological activities [1][2][3]. As many of these compounds feature asymmetric carbon atoms at the α-position of the cyclic amine, the stereoselective carbon–carbon bond formation at this position is of great importance from the perspective of drug discovery [4][5]. Meanwhile the “cation

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

• discovered and designed to competitively inhibit such interactions. Additionally, molecules that are capable of insertion between the DNA base pairs can also disfavor DNA–protein interactions directly or allosterically. Consequently, small molecule DNA binders have been in the limelight of drug-discovery

• the linkers should be carefully investigated when combining fragments in drug discovery applications [123]. Recently, Picconi et al. reported a series of nontoxic triaryl benzimidazole conjugates derived from existing classes of MGBs, to probe their antibacterial activity against multidrug resistant

Fluorocyclisation via I(I)/I(III) catalysis: a concise route to fluorinated oxazolines

• Felix Scheidt,
• Christian Thiehoff,
• Gülay Yilmaz,
• Stephanie Meyer,
• Constantin G. Daniliuc,
• Gerald Kehr and
• Ryan Gilmour

Beilstein J. Org. Chem. 2018, 14, 1021–1027, doi:10.3762/bjoc.14.88

• -ray crystallographic analysis of a representative example. Given the importance of fluorine in drug discovery, its ability to modulate conformation, and the prevalence of the 2-oxazoline scaffold in Nature, this strategy provides a rapid entry into an important bioisostere class. Keywords: catalysis

An efficient and facile access to highly functionalized pyrrole derivatives

• Meng Gao,
• Wenting Zhao,
• Hongyi Zhao,
• Ziyun Lin,
• Dongfeng Zhang and
• Haihong Huang

Beilstein J. Org. Chem. 2018, 14, 884–890, doi:10.3762/bjoc.14.75

• polysubstituted pyrrole compounds, which can deliver potentially valuable building blocks serving as precursors for drug discovery. Further research on the development of more diversified pyrrolo[3,4-c]pyrrole-1,3-diones and more complicated polysubstituted pyrroles is currently underway in our laboratory

Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

• Kartik Temburnikar and
• Katherine L. Seley-Radtke

Beilstein J. Org. Chem. 2018, 14, 772–785, doi:10.3762/bjoc.14.65

• syntheses have contributed to structural diversity and drug discovery efforts. Convergent and modular approaches to synthesis have garnered much attention in this regard. Among them nucleophilic substitution at C1' has seen wide applications providing flexibility in synthesis, good yields, the ability to

• pyrrolo[2,1-f]triazine C-nucleosides (GS-5734 and GS-6620) [32][63][64][65]. Thus, this review attempts to capture the progress in the synthesis efforts and subsequent drug discovery of the C-nucleosides over the past few years. In the first section, the structural and stereochemical underpinnings of

• of their synthesis have become critical to more effective drug discovery. For example, the pyrrolo[2,1-f][1,2,4]triazine scaffold has been key to the discovery of several highly active molecules [53][69][71][72][73][86]. Modular and convergent synthetic routes have proved valuable in this regard both

Fluorogenic PNA probes

• Tirayut Vilaivan

Beilstein J. Org. Chem. 2018, 14, 253–281, doi:10.3762/bjoc.14.17

• areas, including clinical diagnostics and drug discovery amongst others. Molecular probes generally consist of a recognition element that can bind to the specific target, and a reporter group that, in combination with an appropriate signal transduction mechanism, translates the molecular interaction

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• ], protein kinase inhibitors [32], antiallergic [33], antioxidant [34] and as fungicide [35]. Also, the pyrazolo[3,4-b]pyridine ring system is a key structure in drug discovery and has become the main component in many medicinally important compounds. The large number of synthetic routes to pyrazolo[3,4-b

Regioselective decarboxylative addition of malonic acid and its mono(thio)esters to 4-trifluoromethylpyrimidin-2(1H)-ones

• Sergii V. Melnykov,
• Andrii S. Pataman,
• Yurii V. Dmytriv,
• Svitlana V. Shishkina,
• Mykhailo V. Vovk and
• Volodymyr A. Sukach

Beilstein J. Org. Chem. 2017, 13, 2617–2625, doi:10.3762/bjoc.13.259

• modern drug discovery and development area [9][10]. As a result of intensive research efforts over the last decades, efficient fluorination and fluoroalkylation methods have emerged to prepare previously challenging molecules decorated with fluorine atoms or fluorinated groups which make them practically

What contributes to an effective mannose recognition domain?

• Christoph P. Sager,
• Deniz Eriş,
• Martin Smieško,
• Rachel Hevey and
• Beat Ernst

Beilstein J. Org. Chem. 2017, 13, 2584–2595, doi:10.3762/bjoc.13.255

• killing by immune factors, bacteriolytic enzymes, or antibiotics. In this review, with focus on lectins relevant for drug discovery and development, the mannose-binding sites of six CLECs and three bacterial lectins are analyzed and compared with one another to answer the question: What makes for a

Solvent-free copper-catalyzed click chemistry for the synthesis of N-heterocyclic hybrids based on quinoline and 1,2,3-triazole

• Martina Tireli,
• Silvija Maračić,
• Stipe Lukin,
• Marina Juribašić Kulcsár,
• Dijana Žilić,
• Mario Cetina,
• Ivan Halasz,
• Silvana Raić-Malić and
• Krunoslav Užarević

Beilstein J. Org. Chem. 2017, 13, 2352–2363, doi:10.3762/bjoc.13.232

• time, the 1,2,3-triazoles became the heterocycle of choice in drug discovery, due to their favourable pharmacokinetic and safety profiles, hydrogen-bonding capability, moderate dipole moment, rigidity and stability under in vivo conditions [5][6]. Also, the ability of 1,2,3-triazoles to act as amide

High-speed vibration-milling-promoted synthesis of symmetrical frameworks containing two or three pyrrole units

• Marco Leonardi,
• Mercedes Villacampa and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2017, 13, 1957–1962, doi:10.3762/bjoc.13.190

• , which are of interest in the exploration of chemical space for drug discovery purposes. The method was also extended to the synthesis of one compound containing three identical pyrrole fragments via a pseudo-seven-component reaction. Access to compounds having a double bond in their spacer chain was

• by two or more pharmacophoric units joined by a spacer are very important in drug discovery because many drug targets are symmetrical, the reason most often being that they are composed by two or more identical subunits. Some examples of therapeutic targets in which symmetrical bivalent ligands have

• vibration milling (HSVM) [14][15]. The importance of pyrrole frameworks stems from the status of this heterocycle as a privileged structure in drug discovery due to its presence as a structural core in molecules that are able to bind various receptors [16]. Results and Discussion Our route to the target

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• variations are adopted to improve the efficiency of this reaction for practical application towards drug discovery [126][127][128]. Modifications have been done in substrates by replacing urea with substituted ureas and thio urea, use of various 1,3-dicarbonyl compounds etc. Reactions using ionic liquids as

Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz–Fritsch–Bobbitt reaction with non-activated and moderately-activated systems

• Marco Mottinelli,
• Mathew P. Leese and
• Barry V. L. Potter

Beilstein J. Org. Chem. 2017, 13, 1871–1878, doi:10.3762/bjoc.13.182

• Marco Mottinelli Mathew P. Leese Barry V. L. Potter Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, BA2 7AY Bath, UK Drug Discovery & Medicinal Chemistry, Department of Pharmacology, University of Oxford, Mansfield Road

BODIPY-based fluorescent liposomes with sesquiterpene lactone trilobolide

• Ludmila Škorpilová,
• Silvie Rimpelová,
• Michal Jurášek,
• Miloš Buděšínský,
• Jana Lokajová,
• Roman Effenberg,
• Petr Slepička,
• Tomáš Ruml,
• Eva Kmoníčková,
• Pavel B. Drašar and
• Zdeněk Wimmer

Beilstein J. Org. Chem. 2017, 13, 1316–1324, doi:10.3762/bjoc.13.128

• body. This approach has become the key issue for surpassing the bottleneck of drug discovery. With the advent of new technologies and deeper understanding of the biological processes, the concept of specific targeting has become one of the most attractive directions in the field of biomedicine

Aqueous semisynthesis of C-glycoside glycamines from agarose

• Juliana C. Cunico Dallagnol,
• Alexandre Orsato,
• Diogo R. B. Ducatti,
• Miguel D. Noseda,
• Maria Eugênia R. Duarte and
• Alan G. Gonçalves

Beilstein J. Org. Chem. 2017, 13, 1222–1229, doi:10.3762/bjoc.13.121

• employed in drug discovery. A part of our group has utilized this type of approach for the synthesis of dihydropyridine glycoconjugates [9] and antiviral sulfated alkylglycosides [10]. In an effort to amplify the utility of AnGal as a starting material for the synthesis of bioactive compounds, we have

An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-derived building blocks

• Sushil K. Maurya and
• Rohit Rana

Beilstein J. Org. Chem. 2017, 13, 1106–1118, doi:10.3762/bjoc.13.110

• rings and have shown important biological properties [5][6][7][8][9][10][11][12]. For example, macrocyclic aminoglycoside analogues have shown binding with the trans-activating region (TAR) RNA of the human immunodeficiency virus (HIV); an attractive target for RNA-based drug discovery [13]. Further

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

• multistep flow synthesis needs to be carried out to enhance the productivity and reliability of a synthesis protocol. Automation in lab-scale environment: Automation can significantly improve the productivity of lab scale experiments and also aid speeding up the synthesis of a library of compounds and drug

• discovery process [47]. The chemical library has to go through high-throughput screening (about 100,000 compounds/day approximately) using robots [48]. In multistep synthesis off-line analysis actually becomes a bottleneck as it does not allow the real-time changes to be imposed at the inlet conditions for

Chemoselective synthesis of diaryl disulfides via a visible light-mediated coupling of arenediazonium tetrafluoroborates and CS₂

• Jing Leng,
• Shi-Meng Wang and
• Hua-Li Qin

Beilstein J. Org. Chem. 2017, 13, 903–909, doi:10.3762/bjoc.13.91

• tetrafluoroborates; carbon disulfide; chemoselectivity; diaryl disulfides; photocatalyst; Findings The development of methods for the functionalization of peptides and proteins under mild conditions is a current frontier in the fields of chemistry, biology and drug discovery [1][2][3][4]. Most of the