Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• bioavailability of a drug molecule; this concept is explored in the next section. 5. Fluorination alters the basicity of N-heterocycles The 3-piperidinylindole derivative 38 (Table 1) binds to the human 5-HT2A serotonin receptor, and was identified as a promising antipsychotic drug lead [48]. However, the

• bioavailability of 38 was poor, and this was attributed to the basicity of the secondary amine group which made the molecule positively charged at physiological pH and hence unable to traverse biological membranes. This problem was overcome by introducing a fluorine atom onto the piperidine ring (39): the

• basicity of the secondary amine was thereby reduced by nearly two orders of magnitude, and this led to a marked improvement in bioavailability. Incidentally, it is also worthy of note that the bioavailability (and 5-HT2A binding affinity) could be further improved by the introduction of a second fluorine

Recent advances in transition metal-catalyzed Csp²-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

• Grégory Landelle,
• Armen Panossian,
• Sergiy Pazenok,
• Jean-Pierre Vors and
• Frédéric R. Leroux

Beilstein J. Org. Chem. 2013, 9, 2476–2536, doi:10.3762/bjoc.9.287

• . Perfluoroalkyl substituents are particularly interesting as they often lead to a significant increase in lipophilicity and thus bioavailability albeit with a modified stability. Therefore, it is of continual interest to develop new, environmentally benign methods for the introduction of these groups into target

Cu-catalyzed trifluoromethylation of aryl iodides with trifluoromethylzinc reagent prepared in situ from trifluoromethyl iodide

• Yuzo Nakamura,
• Motohiro Fujiu,
• Tatsuya Murase,
• Yoshimitsu Itoh,
• Hiroki Serizawa,
• Kohsuke Aikawa and
• Koichi Mikami

Beilstein J. Org. Chem. 2013, 9, 2404–2409, doi:10.3762/bjoc.9.277

• , biological, and physical properties [1][2][3][4][5][6]. Particularly, trifluoromethylated compounds can be widely employed as one of the most effective analogues of bioactive compounds, because the trifluoromethyl group enhances the metabolic stability, lipophilicity, and bioavailability of these compounds

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• alkyl chain to moderate their bioavailability resulting in the ultimate discovery of tiagabine (2.36) which has an embedded (R)-nipecotate unit as the class indicative pharmacophore. The synthesis of tiagabine (2.36) is readily accomplished by the union of ethyl nipecotate with the bis-thiophene

Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

• Allison S. Limpert,
• Margrith E. Mattmann and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2013, 9, 717–732, doi:10.3762/bjoc.9.82

• stability and oral bioavailability, as well as high brain accumulation [33]. Due to its advantageous pharmacological properties, 14 was tested in SOD1 G93A transgenic mice to determine whether it was able to extend lifespan and alleviate symptoms in a mouse model of ALS. However, this compound demonstrated

• 16 was found to be highly active in both of these assays and additionally demonstrated high potency and low toxicity, as well as excellent solubility and plasma stability [35]. Further studies indicated that compound 16 was able to cross the BBB and exhibited good oral bioavailability [35]. An

Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis

• Stephan Klopries,
• Uschi Sundermann and
• Frank Schulz

Beilstein J. Org. Chem. 2013, 9, 664–674, doi:10.3762/bjoc.9.75

• . Especially the bioavailability and the coupled acceptance efficiency to the corresponding CoA-esters remain to be clarified. This has recently become highly relevant, as the first example for an acyltransferase domain with artificially broadened substrate specificity has been constructed and introduced in

Asymmetric synthesis of host-directed inhibitors of myxoviruses

• Terry W. Moore,
• Kasinath Sana,
• Dan Yan,
• Pahk Thepchatri,
• John M. Ndungu,
• Manohar T. Saindane,
• Mark A. Lockwood,
• Michael G. Natchus,
• Dennis C. Liotta,
• Richard K. Plemper,
• James P. Snyder and
• Aiming Sun

Beilstein J. Org. Chem. 2013, 9, 197–203, doi:10.3762/bjoc.9.23

• bioavailability [15]. Additionally, it was shown that the methyl group at the stereogenic center alpha to the carbonyl is important for biological activity [8][12][14]. Compound 1 was previously prepared as the racemate, but subsequently separated into enantiomers by chiral HPLC. To enable large-scale preparation

Theoretical study on β-cyclodextrin inclusion complexes with propiconazole and protonated propiconazole

• Adrian Fifere,
• Narcisa Marangoci,
• Stelian Maier,
• Adina Coroaba,
• Dan Maftei and
• Mariana Pinteala

Beilstein J. Org. Chem. 2012, 8, 2191–2201, doi:10.3762/bjoc.8.247

• modified (by pegylation for example) in order to avoid the shielding of the cavity during the inclusion process, and, as a consequence, to improve the systemic bioavailability and pharmacokinetics of the inclusion complexes. Results and Discussions The most stable conformations of the β-CD/PP and β-CD/PPH

Hydrophobic analogues of rhodamine B and rhodamine 101: potent fluorescent probes of mitochondria in living C. elegans

• Laurie F. Mottram,
• Safiyyah Forbes,
• Brian D. Ackley and
• Blake R. Peterson

Beilstein J. Org. Chem. 2012, 8, 2156–2165, doi:10.3762/bjoc.8.243

• , that are targeted to this organelle. In general, the choice to use small-molecule probes or molecular-biology-based approaches for these types of imaging applications can be challenging because of our limited understanding of the bioavailability and bioaccumulation of small molecules in this model

• agents must be added to C. elegans at concentrations orders of magnitude higher than are used with mammalian cells in culture [35][36]. For some hydrophobic compounds, delivery systems [31][32] can improve their uptake. We hypothesized that poor bioavailability of rhodamines in C. elegans may be

Cyclodextrin-based nanosponges as drug carriers

• Francesco Trotta,
• Marco Zanetti and
• Roberta Cavalli

Beilstein J. Org. Chem. 2012, 8, 2091–2099, doi:10.3762/bjoc.8.235

• molecules is widely used in the pharmaceutical field as a strategy to increase the aqueous solubility and, consequently, bioavailability of lipophilic drugs. For hydrophilic or moderately polar drugs this approach is less effective, and consequently cyclodextrin derivatives have been investigated

• formulation and bioavailability problems can be solved by enhancing the solubility and dissolution rate of a substance, and nanosponges can greatly enhance the drug solubility. Swaminathan et al. studied a formulation of itraconazole in nanosponges [33], a drug with an aqueous solubility of about 1 ng/mL at

• available on the market. Nanosponge formulation could thus increase the bioavailability of itraconazole. The solubilisation efficiency of nanosponges with regard to tamoxifen, a nonsteroidal anti-estrogen molecule used for treating and preventing breast cancer, was observed by using a 0.5% aqueous

Total synthesis and biological evaluation of fluorinated cryptophycins

• Christine Weiß,
• Tobias Bogner,
• Benedikt Sammet and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 2060–2066, doi:10.3762/bjoc.8.231

• [10][11]. Fluorinated drugs are gaining increasing importance, and currently about 20% of all pharmaceuticals on the world market contain fluorine substituents [12][13]. Fluorination is supposed to enhance bioavailability and receptor selectivity. The van der Waals-radius of a fluorine substituent

Dimerization of a cell-penetrating peptide leads to enhanced cellular uptake and drug delivery

• Jan Hoyer,
• Ulrich Schatzschneider,
• Michaela Schulz-Siegmund and
• Ines Neundorf

Beilstein J. Org. Chem. 2012, 8, 1788–1797, doi:10.3762/bjoc.8.204

• potential due to limited bioavailability and cellular uptake. In recent years, cell-penetrating peptides (CPPs) emerged as an encouraging tool to overcome this obstacle owing to their ability to autonomously cross the cellular membrane in a receptor-independent manner. This enables them to deliver a large

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

• -chemical space of synthetic drug-like small molecules focusing on 6,5-heterobicyclic ring systems in order to increase the diversity of our proprietary compound library [13]. Criteria for selection of the target structures include the potential for biological activity and bioavailability (peroral, and

• suitable range for perorally active drugs. A pKa value of 10.0, and a logP value of 3 was determined. Thus, the molecule will be uncharged under physiological conditions and the logP value is in a range which allows us to predict oral bioavailability [29]. Conclusion In conclusion, we have designed and

Similarity analysis, synthesis, and bioassay of antibacterial cyclic peptidomimetics

• Workalemahu M. Berhanu,
• Mohamed A. Ibrahim,
• Girinath G. Pillai,
• Alexander A. Oliferenko,
• Levan Khelashvili,
• Farukh Jabeen,
• Bushra Mirza,
• Farzana Latif Ansari,
• Ihsan ul-Haq,
• Said A. El-Feky and
• Alan R. Katritzky

Beilstein J. Org. Chem. 2012, 8, 1146–1160, doi:10.3762/bjoc.8.128

• free carboxylic groups. It is reasonable to assume that such a zwitter-ionic structure alters the charge distribution and also eliminates hydrogen bonding in which the pyridine nitrogen atom acts as a H-bond acceptor. These factors increase hydrophobicity and thus deteriorate bioavailability, as

Algicidal lactones from the marine Roseobacter clade bacterium Ruegeria pomeroyi

• Ramona Riclea,
• Julia Gleitzmann,
• Hilke Bruns,
• Corina Junker,
• Barbara Schulz and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2012, 8, 941–950, doi:10.3762/bjoc.8.106

• bioavailability of metal ions by the formation of metal–MeSH complexes [7] and can be used for the biosynthesis of various sulfur-containing secondary metabolites [20]. A sulfur-containing metabolite, for which the direct sulfur precursor has not been determined yet, is the antibiotic tropodithietic acid (TDA, 2

Synthesis and antifungal properties of papulacandin derivatives

• Marjolein van der Kaaden,
• Eefjan Breukink and
• Roland J. Pieters

Beilstein J. Org. Chem. 2012, 8, 732–737, doi:10.3762/bjoc.8.82

• fungal infections in immunocompromised patients has been observed [1]. Treatment failure is frequent and mortality is unacceptably high in high-risk patients [2]. Reasons for this include delayed diagnosis, toxicity and low bioavailability of current drugs, and the development of antifungal drug

Investigation of the network of preferred interactions in an artificial coiled-coil association using the peptide array technique

• Raheleh Rezaei Araghi,
• Carsten C. Mahrenholz,
• Rudolf Volkmer and
• Beate Koksch

Beilstein J. Org. Chem. 2012, 8, 640–649, doi:10.3762/bjoc.8.71

• the concept of rational drug design based on coiled-coil proteins [6]. In this context, the use of unnatural amino acids in peptidomimetics is advisable, to enhance enzymatic stability, limit conformational flexibility, and improve pharmacodynamics and bioavailability [7]. In order to manipulate helix

Advances in synthetic approach to and antifungal activity of triazoles

• Kumari Shalini,
• Nitin Kumar,
• Sushma Drabu and
• Pramod Kumar Sharma

Beilstein J. Org. Chem. 2011, 7, 668–677, doi:10.3762/bjoc.7.79

• metabolism. Fluconazole (9) has nearly complete oral bioavailability, circulates in plasma as the free form, shows negligible hepatic metabolism, and is excreted unchanged through the kidneys. Itraconazole (10) is well absorbed by the gastrointestinal tract, high protein binding extensive hepatic metabolism

• , and is excreted in an inactive form via liver and kidneys. Fluconazole is 94% absorbed and its oral bioavailability is not affected by food or gastric pH. It is excreted unchanged in urine with t1/2 = 25–30 h. Itraconazole is largely metabolized in liver by cytochrome P450 3A4, an active metabolite is

• in the abdomen, kidney, bladder wall and wounds, and infections caused by Scedosporium apiospermum and Fusarium spp [51]. Voriconazole is available for both oral as well as intravenous (i.v.) administration and has excellent bioavailability (90%). It is metabolized in the liver and, in case of renal

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• II receptor were of a peptidic nature, suffered from poor bioavailability and also showed some agonistic activities. The first non-peptide antagonists were developed in the early 80’s. Although these compounds were selective for the AT2 receptor, they bound only weakly to their target protein. On

• suffer from poor absorption and low bioavailability. At this stage a classical bioisostere exchange, i.e., replacing a carboxylic acid group with a tetrazole ring, was performed which resulted in increased lipophilicity [48] and the development of the orally active losartan. In the absence of a crystal

Oxalyl retro-peptide gelators. Synthesis, gelation properties and stereochemical effects

• Janja Makarević,
• Milan Jokić,
• Leo Frkanec,
• Vesna Čaplar,
• Nataša Šijaković Vujičić and
• Mladen Žinić

Beilstein J. Org. Chem. 2010, 6, 945–959, doi:10.3762/bjoc.6.106

• characteristics of gels formed by chiral bis(dipeptide)oxalamides. Structurally, such gelators belong to the group of retro-peptides, which have been intensively studied as peptidomimetics due to their higher proteolytic stability and bioavailability compared to natural counterparts [44][45][46][47]. Despite very

Synthesis of glycosylated β³-homo-threonine conjugates for mucin-like glycopeptide antigen analogues

• Florian Karch and
• Anja Hoffmann-Röder

Beilstein J. Org. Chem. 2010, 6, No. 47, doi:10.3762/bjoc.6.47

• bioavailability for tumour immunotherapy. Towards this end, TN and TF antigen conjugates O-glycosidically linked to Fmoc-β3-homo-threonine were prepared in good yield via Arndt–Eistert homologation of the corresponding glycosyl α-amino acid derivative. By incorporation of TN-Fmoc-β3hThr conjugate into the 20

Efficient and improved synthesis of Telmisartan

• A. Sanjeev Kumar,
• Samir Ghosh and
• G. N. Mehta

Beilstein J. Org. Chem. 2010, 6, No. 25, doi:10.3762/bjoc.6.25

• , all of which contain a characteristic ortho functionalized biaryl moiety. Telmisartan (1, Boehringer Ingelheim, Micardis®) (Figure 1) is an important member of this class of top-selling drugs because it has the strongest binding affinity to the AT1 receptor, an excellent bioavailability, and a once

(Pseudo)amide-linked oligosaccharide mimetics: molecular recognition and supramolecular properties

• José L. Jiménez Blanco,
• Fernando Ortega-Caballero,
• Carmen Ortiz Mellet and
• José M. García Fernández

Beilstein J. Org. Chem. 2010, 6, No. 20, doi:10.3762/bjoc.6.20

• blocks is inspired by the structure of peptides and the potential of carbohydrates to reproduce the structural features and biological properties of these polymers [12][13][17]. Poor bioavailability and metabolic stability of peptides have resulted in significant limitations as drug candidates. Another

Synthesis and enzymatic evaluation of 2- and 4-aminothiazole- based inhibitors of neuronal nitric oxide synthase

• Graham R. Lawton,
• Haitao Ji,
• Pavel Martásek,
• Linda J. Roman and
• Richard B. Silverman

Beilstein J. Org. Chem. 2009, 5, No. 28, doi:10.3762/bjoc.5.28

• protonated for this interaction to occur. Replacement of the aminopyridine with less basic aminothiazoles (3 and 4), whose ring nitrogens have pKa values ≈ 6, should reduce the overall charge on the molecule at physiological pH for more efficient bioavailability. In the acidic environment of the nNOS active

Enantioselective nucleophilic difluoromethylation of aromatic aldehydes with Me₃SiCF₂SO₂Ph and PhSO₂CF₂H reagents catalyzed by chiral quaternary ammonium salts

• Chuanfa Ni,
• Fang Wang and
• Jinbo Hu

Beilstein J. Org. Chem. 2008, 4, No. 21, doi:10.3762/bjoc.4.21

• this field. Background Because of the unique properties of fluorine, selective introduction of fluorine atom(s) or fluorine-containing moieties into organic molecules often dramatically alter their stability, lipophilicity, bioavailability, and biopotency. It is estimated that as many as 30–40% of