- Structural spectroscopic study of enantiomerically pure synthetic cathinones and their major metabolites
-
New psychoactive substances (NPSs) have become a popular alternative to illicit drugs of abuse. However, to determine their metabolic pathways in the human organism, a detailed knowledge of their structure is crucial. Here, we present a comprehensive spectroscopic structural study of synthetic cathinones (clephedrone, flephedrone, and brephedrone) and their major human metabolites, desmethyl derivatives. Chiral high-performance liquid chromatography was utilized to obtain the individual enantiomers of the parent synthetic cathinones and their assumed major metabolites synthesized de novo. The developed chromatographic method made it possible to obtain the target optically pure substances on a multimilligram scale. Electronic and vibrational circular dichroism, combined with infrared and ultraviolet spectroscopy and supported by DFT calculations, were used to determine their absolute configuration and the chiroptical methods to elucidate their molecular structure in detail. Two stable conformers of each substance were found in aqueous solution. Their relative abundances were estimated based on the Boltzmann distribution and the population weighted spectra were obtained. Very good agreement was achieved between the experimental and simulated spectra, enabling the 3D structures of the studied substances to be determined in aqueous solution. This journal is
- Spálovská, Dita,Pa?kan, Martin,Jurásek, Bronislav,Kucha?, Martin,Kohout, Michal,Setni?ka, Vladimír
-
supporting information
p. 850 - 860
(2021/01/25)
-
- Fragment splicing-based design, synthesis and safener activity of novel substituted phenyl oxazole derivatives
-
Fragment splicing is a primary strategy in the design and optimization of leading compound toward new skeleton with target bioactivity. Herein a series of novel substituted phenyl oxazole derivatives were designed via fragment analysis and coupling strategy that led to highly potent and bio-selective herbicide safener. The biological tests showed that most of the compounds could enhance the maize growth index, glutathione content and anti-reverse enzyme glutathione S-transferase activity in vivo. The molecular docking model exhibited that the novel compound could compete with chlorsulfuron binding to the herbicide target enzyme, which consequently attained the herbicide detoxification. Especially compound I-f displayed the best activities than commercial safener isoxadifen-ethyl and other compounds. The present work demonstrates that the synthesized compounds could be developed as potential candidates for the discovery of novel herbicide safeners in the future.
- Fu, Ying,Zhang, Dong,Kang, Tao,Guo, You-Yuan,Chen, Wen-Geng,Gao, Shuang,Ye, Fei
-
p. 570 - 576
(2019/01/04)
-
- Design, synthesis and broad-spectrum Bcr-Abl inhibitory activity of novel thiazolamide-benzamide derivatives
-
Bcr-Abl plays an important role in the pathogenesis and development of chronic myeloid leukemia (CML). But Bcr-Abl is prone to mutation, so it increases the difficulty of clinical treatment. Therefore, it is crucial to design a new class of broad-spectrum Bcr-Abl inhibitors. Herein, forty novel thiazolamide-benzamide derivatives were synthesized and evaluated their broad-spectrum Bcr-Abl inhibitory activities. The newly synthesized compounds were characterized by using spectrum data (1H NMR, APCI-MS and IR) and elemental analysis. The protein kinase results indicated that eight compounds (3a, 3e, 3m, 3n, 3p, 4c, 4f, 4g) showed high activities to wild-type and T315I mutation. The most potent compound 3m exhibited an Abl IC50 value as low as 1.273 μM and showed inhibition to the T315I mutant with IC50 value 39.89 μM. 3m could prove to be a new promising lead compound for the further development of broad-spectrum Bcr-Abl inhibitors to overcome clinical acquired resistance.
- Liu, Juan,Huang, Honglin,Deng, Xiangping,Xiong, Runde,Cao, Xuan,Tang, Guotao,Wu, Xin,Xu, Shiyu,Peng, Junmei
-
p. 2092 - 2101
(2019/01/26)
-
- Formal Total Synthesis of Hybocarpone Enabled by Visible-Light-Promoted Benzannulation
-
The formal total synthesis of hybocarpone was achieved in eight steps from commercially available 1,2,4-trimethoxybenzene. Key transformations include a visible-light-promoted benzannulation to construct the key α-naphthol intermediate and a modified CAN-mediated dimerization/hydration cascade sequence to generate the vicinal all-carbon quaternary centers in a stereocontrolled manner. The total synthesis of boryquinone was also achieved in seven steps.
- Chen, Wei,Guo, Renyu,Yang, Zhen,Gong, Jianxian
-
p. 15524 - 15532
(2019/01/03)
-
- INDOLE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
-
The present disclosure relates to compounds and a pharmaceutically acceptable salt thereof, compositions, combinations and medicaments containing the compounds, and processes for their preparation. The disclosure also relates to the use of the compounds, combinations, compositions and medicaments, for example as inhibitors of the activity of the estrogen receptor, including degrading the estrogen receptor, the treatment of diseases and conditions mediated by the estrogen receptor.
- -
-
Paragraph 0409; 0410
(2018/04/21)
-
- Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools
-
The most common CF mutation, F508del, impairs the processing and gating of CFTR protein. This deletion results in the improper folding of the protein and its degradation before it reaches the plasma membrane of epithelial cells. Present correctors, like VX809 only induce a partial rescue of the mutant protein. Our previous studies reported a class of compounds, called aminoarylthiazoles (AATs), featuring an interesting activity as correctors. Some of them show additive effect with VX809 indicating a different mechanism of action. In an attempt to construct more interesting molecules, it was thought to generate chemically hybrid compounds, blending a portion of VX809 merged to the thiazole scaffold. This approach was guided by the development of QSAR analyses, which were performed based on the F508del correctors so far disclosed in the literature. This strategy was aimed at exploring the key requirements turning in the corrector ability of the collected derivatives and allowed us to derive a predictive model guiding for the synthesis of novel hybrids as promising correctors. The new molecules were tested in functional and biochemical assays on bronchial CFBE41o-cells expressing F508del-CFTR showing a promising corrector activity.
- Liessi, Nara,Cichero, Elena,Pesce, Emanuela,Arkel, Maria,Salis, Annalisa,Tomati, Valeria,Paccagnella, Matteo,Damonte, Gianluca,Tasso, Bruno,Galietta, Luis J.V.,Pedemonte, Nicoletta,Fossa, Paola,Millo, Enrico
-
p. 179 - 200
(2017/12/28)
-
- Annulation Cascades of 2-Bromo-1-arylpropan-1-ones with Terminal Alkynes Involving C-Br/C-H Functionalization
-
Straightforward access to various substituted naphthalenones by copper-catalyzed [4 + 2] annulation cascades of 2-bromo-1-arylpropan-1-ones with terminal alkynes is presented. Employing a Cu(MeCN)4PF4 catalyst and 1,10-phenanthroline (1,10-Phen) ligand enables the formation of three new C-C bonds in a single reaction via [4 + 2] annulation of a 2-bromo-1-arylpropan-1-one with an alkyne followed by α-alkylation with the other 2-bromo-1-arylpropan-1-one with excellent functional group tolerance and step efficiency.
- Ouyang, Xuan-Hui,Hu, Chao,Song, Ren-Jie,Li, Jin-Heng
-
supporting information
p. 4659 - 4662
(2018/08/09)
-
- Discovery of 3,5-Diphenyl-4-methyl-1,3-oxazolidin-2-ones as Novel, Potent, and Orally Available Δ-5 Desaturase (D5D) Inhibitors
-
The discovery and optimization of Δ-5 desaturase (D5D) inhibitors are described. Investigation of the 1,3-oxazolidin-2-one scaffold was inspired by a pharmacophore model constructed from the common features of several hit compounds, resulting in the identification of 3,5-diphenyl-1,3-oxazolidin-2-one 5h as a novel lead showing potent in vitro activity. Subsequent optimization focused on the modification of two metabolic sites, which provided (4S,5S)-5i, a derivative with improved metabolic stability. Moreover, adding a substituent into the upper phenyl moiety further enhanced the intrinsic activity, which led to the discovery of 5-[(4S,5S)-5-(4fluorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]benzene-1,3-dicarbonitrile (4S,5S)-5n, endowed with excellent D5D binding affinity, cellular activity, and high oral bioavailability in a mouse. It exhibited robust in vivo hepatic arachidonic acid/dihomo-γ-linolenic acid ratio reduction (a target engagement marker) in an atherosclerosis mouse model. Finally, an asymmetric synthetic procedure for this compound was established.
- Fujimoto, Jun,Okamoto, Rei,Noguchi, Naoyoshi,Hara, Ryoma,Masada, Shinichi,Kawamoto, Tetsuji,Nagase, Hiroki,Tamura, Yumiko Okano,Imanishi, Mitsuaki,Takagahara, Shuichi,Kubo, Kazuki,Tohyama, Kimio,Iida, Koichi,Andou, Tomohiro,Miyahisa, Ikuo,Matsui, Junji,Hayashi, Ryouta,Maekawa, Tsuyoshi,Matsunaga, Nobuyuki
-
p. 8963 - 8981
(2017/11/14)
-
- Enantioselective and Diastereoselective Construction of Chiral Amino Alcohols by Iridium-f-Amphox-Catalyzed Asymmetric Hydrogenation via Dynamic Kinetic Resolution
-
The iridium-f-amphox-catalyzed asymmetric hydrogenation of racemic α-amino β-unfunctionalized ketones proceeds via a DKR (dynamic kinetic resolution) process for the construction of various chiral N,N-disubstituted α-amino β-unfunctionalized alcohols in quantitative yields with excellent enantioselectivities and diastereoselectivities (all products >99% ee and >99:1 dr, TON up to 100 000). Importantly, this catalytic asymmetric hydrogenation with a DKR process provided a highly efficient and powerful synthetic strategy for the preparation of key chiral intermediates of the preclinical antitumor agent (S,S)-R116010.
- Wu, Weilong,You, Cai,Yin, Congcong,Liu, Yuanhua,Dong, Xiu-Qin,Zhang, Xumu
-
supporting information
p. 2548 - 2551
(2017/05/24)
-
- A Platform of Regioselective Methodologies to Access Polysubstituted 2-Methyl-1,4-naphthoquinone Derivatives: Scope and Limitations
-
A platform of synthetic methodologies has been established to access a focused library of polysubstituted 3-benzylmenadione derivatives functionalized on the aromatic ring of the naphthoquinone core. Two main routes were explored: 1) The naphthol route, starting from either an α-tetralone or a propiophenone, and 2) the regioselective Diels-Alder reaction, starting from various dienes and two 2-bromo-5(or 6)-methyl-1,4-benzoquinones. 6-Substituted 2-methylnaphthols were synthesized by using a xanthate-mediated free-radical addition/cyclization sequence for the construction of the 6-substituted menadione subunit. Furthermore, an efficient and simple new pathway that allows the formation of 6- or 7-substituted 3-(substituted-benzyl)menadione regioisomers from a common commercial scaffold has also been developed by the naphthol route, advantageous with regard to step economy. Our synthetic methodologies exemplified by 34 compounds have allowed structure-activity relationships to be deduced for use as the basis for the development of new antimalarial redox-active polysubstituted benzylmenadione derivatives.
- Rodo, Elena Cesar,Feng, Liwen,Jida, Mouhamad,Ehrhardt, Katharina,Bielitza, Max,Boilevin, Jérémy,Lanzer, Michael,Williams, David Lee,Lanfranchi, Don Antoine,Davioud-Charvet, Elisabeth
-
supporting information
p. 1982 - 1993
(2016/04/26)
-
- Stereodivergent Synthesis of Chromanones and Flavanones via Intramolecular Benzoin Reaction
-
The strategy of stereodivergent reactions on racemic mixtures (stereodivergent RRM) was employed for the first time in intramolecular benzoin reactions and led to the rapid access of chromanones/flavanones with two consecutive stereocenters. The easily separable stereoisomers of the products were obtained with moderate to excellent enantioselectivities in a single step. Catechol type additives proved crucial in achieving the desired diastereo- and enantioselectivities.
- Wen, Genfa,Su, Yingpeng,Zhang, Guoxiang,Lin, Qiqiao,Zhu, Yujin,Zhang, Qianqian,Fang, Xinqiang
-
supporting information
p. 3980 - 3983
(2016/09/09)
-
- TOTAL SYNTHESIS OF REDOX-ACTIVE 1.4-NAPHTHOQUINONES AND THEIR METABOLITES AND THEIR THERAPEUTIC USE AS ANTIMALARIAL AND SCHISTOMICIDAL AGENTS
-
Naphthoquinones, azanaphthoquinones and benxanthones, their process of synthesis and their use as antimalarial or antischistosomal agents.
- -
-
Page/Page column 77-78
(2012/10/18)
-
- Total synthesis of redox-active 1.4-naphthoquinones and their metabolites and their therapeutic use as antimalarial and schistomicidal agents
-
Naphthoquinones, azanaphthoquinones and benxanthones, their process of synthesis and their use as antimalarial or antischistosomal agents.
- -
-
Paragraph 0110-0115
(2013/03/26)
-
- Substituted 2-aminothiazoles are exceptional inhibitors of neuronal degeneration in tau-driven models of Alzheimer's disease
-
A novel series of 2-aminothiazoles with strong protection in an Alzheimer's disease (AD) model comprising tau-induced neuronal toxicity is disclosed. These derivatives can be synthesized in one-pot and a small SAR of the substitution within these series afforded several compounds that counteracted tau-induced cell toxicity at nanomolar concentrations. These congeners therefore have strong potential as possible treatment for Alzheimer's disease and other related tauopathies.
- Lagoja, Irene,Pannecouque, Christophe,Griffioen, Gerard,Wera, Stefaan,Rojasdelaparra, Veronica Maria,Van Aerschot, Arthur
-
p. 386 - 392
(2012/05/31)
-
- Substituted Phenylpiperazinyl Aralkylalcohol Derivatives, Pharmaceutical Compositions Containing Such Derivatives and Uses Thereof
-
The invention relates to a substituted phenylpiperazine aryl alkanol derivative represented by the following general formula and its salt and hydrate, wherein C1 and C2 represent chiral carbon atoms, and the compound is one of the six isomers: (1RS, 2SR), (1RS, 2RS), (1R, 2S), (1S, 2S), (1R, 2R) or (1S, 2R); and R, R1, R2, R3 and Ar are as defined in the specification. The derivative is non-opioid analgesic, has good analgesic effect and relatively small side effects. The invention also relates to a composition comprising the derivative and its use.
- -
-
Page/Page column 14
(2011/12/13)
-
- NOVEL COMPOUND HAVING AFFINITY FOR AMYLOID
-
A compound effective as a probe targeting amyloid for image diagnosis and a reagent comprising the compound for detecting amyloid deposited on a biological tissue are provided. Provided are a compound represented by the following formula (1): wherein R1 is a group selected from the group consisting of a halogen substituent, alkyl substituent with 1 to 4 carbon atoms, alkoxy substituent having alkyl chain with 1 to 4 carbon atoms and hydroxyl group, R2 is a group selected from the group consisting of a cyano substituent, alkyl substituent with 1 to 4 carbon atoms and halogen substituent, is a group selected from the group consisting of a hydroxyl group, halogen substituent and substituent represented by the following formula: (wherein R4 is a hydrogen, halogen substituent or hydroxyl group, and m is an integer of 1 to 4), provided that a t least one of R1, R2, R3 and R4 represents a radioactive halogen, and a reagent comprising the same.
- -
-
Page/Page column 11; 25
(2010/08/09)
-
- FUNGICIDAL PYRIDAZINES
-
Disclosed are compounds of Formula 1, including all geometric and stereoisomers, N-oxides, and salts thereof, wherein R1, R2, R3, R4, X, Y and m are as defined in the disclosure. Also disclosed are compositions containing the compounds of Formula 1 and methods for controlling plant disease caused by a fungal pathogen comprising applying an effective amount of a compound or a composition of the invention.
- -
-
Page/Page column 41
(2010/04/27)
-
- COMPOUND FOR INHIBITING TYROSINE KINASE ACTIVITY OF DDR2 PROTEIN
-
A new furopyrimidine compound, their pharmaceutically acceptable salt, and a tyrosine kinase activity inhibitor. The furopyrimidine compound is a compound defined by chemical formula 1, 2, 3 or 4, on their precursor, and can exist as a form of free base or in an acid-addition salt. Since the furopyrimidine compound has an effect of inhibiting activity of DDR2 tyrosine kinase, it can be used in treating illnesses caused by the DDR2 tyrosine kinase activity such as hepatocirrhosis, rheumatoid arthritis or cancer.
- -
-
Page/Page column 30-31
(2010/02/14)
-
- SUBSTITUTED THIAZOLE DERIVATIVES BEARING 3-PYRIDYL GROUPS, PROCESS FOR PREPARING THE SAME AND USE THEREOF
-
The present invention provides a pharmaceutical composition having a steroid C17,20-lyase inhibitory activity, which is useful as a prophylactic or therapeutic agent of prostatism, tumor such as breast cancer and the like, more particularly, a steroid C17,20-lyase inhibitor containing a compound represented by the formula: wherein A1 is an aromatic hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, one of A2 and A3 is a hydrogen atom, a halogen atom, a C1-4 aliphatic hydrocarbon group optionally having substituents or an optionally esterified carboxyl group, the other of A2 and A3 is an aromatic hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, and at least one of A1, A2 and A3 is a 3-pyridyl group optionally having substituents, or a salt thereof or a prodrug thereof.
- -
-
Page/Page column 35
(2008/06/13)
-
- N.C.A. 18F-labelled norephedrine derivatives via α-aminopropiophenones
-
N-protected 2-amino-1-([18F]fluorophenyl)-1-propanones are interesting fluorine-18 labelled intermediates to synthesize potential PET-tracers for mapping the adrenergic nervous system of the heart. Several N-protected α-aminoalkylarylketones were prepared to examine the direct nucleophilic n.c.a. 18F-fluorination of these carbonyl activated precursors. The influence of different protecting groups, the kind of leaving group and the stereoselective reduction of the keto function have been investigated in order to optimize the radiotracer production. It was shown that the 18F-substitution of the para-trimethylammonium group, e.g. of N-dibenzylated propiophenone, leads to radiochemical yields of up to 60%. The stereoselective reduction of the carbonyl function with formation of the n.c.a. erythro 2-N,N-dibenzylamino-1-(4-[18F]fluorophenyl)-1-propanol was performed using BH3·THF. The diastereomeric excess was about 80%. Hydrogenolytical debenzylation was achieved with ammonium formiate in presence of palladium on charcoal to give the 4-[18F]fluoronorephedrine with a radiochemical yield of 15-20% within a total time of 60 min.
- Ermert,Hamacher,Coenen
-
p. 1345 - 1363
(2007/10/03)
-
- 2-PIPERIDINO-1-ALKANOL DERIVATIVES AS NEUROPROTECTIVE AGENTS
-
A method of blocking N-methyl-D-aspartic acid (NMDA) receptor sites in a mammal in need thereof with an effective NMDA blocking (neuroprotective and antiischemic) amount of 2-piperidino-1-alkanol derivatives and 2-azabicyclo-1-alkanol derivatives and analogs and pharmaceutically acceptable salts thereof; methods of using these compounds in the treatment of stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, CNS degenerative diseases such as Alzheimer's disease, senile dementia of the Alzheimer's type, Huntington's disease, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychotic conditions, drug addictions, migraine, hypoglycemia, anxiolytic conditions, urinary incontinence and an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised.
- -
-
-
- (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: A potent new neuroprotectant which blocks N-methyl-D-aspartate responses
-
(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (20, CP-101,606) has been identified as a potent and selective N-methyl-D- aspartate (NMDA) antagonist through a structure activity relation (SAR) program based on ifenprodil, a known antihypertensive agent with NMDA antagonist activity. Sites on the threo-ifenprodil skeleton explored in this report include the pendent methyl group (H, methyl, and ethyl nearly equipotent; propyl much weaker), the spacer group connecting the C-4 phenyl group to the piperidine ring (an alternating potency pattern with 0 and 2 carbon atoms yielding the greatest potency), and simple phenyl substitution (little effect). While potent NMDA antagonists were obtained with a two atom spacer, this arrangement also increased α1 adrenergic affinity. Introduction of a hydroxyl group into the C-4 position on the piperidine ring resulted in substantial reduction in α1 adrenergic affinity. The combination of these observations was instrumental in the discovery of 20. This compound potently protects cultured hippocampal neurons from glutamate toxicity (IC50 = 10 nM) while possessing little of the undesired α1 adrenergic affinity (IC50 ~ 20 μM) of ifenprodil. Furthermore, 20 appears to lack the psychomotor stimulant effects of nonselective competitive and channel-blocking NMDA antagonists. Thus, 20 shows great promise as a neuroprotective agent and may lack the side effects of compounds currently in clinical trials.
- Chenard,Bordner,Butler,Chambers,Collins,De Costa,Ducat,Dumont,Fox,Mena,Menniti,Nielsen,Pagnozzi,Richter,Ronau,Shalaby,Stemple,White
-
p. 3138 - 3145
(2007/10/03)
-
- Nortropyl-1-alkanol derivatives as antiischemic agents
-
2-(8-Azabicyclo[3.2.1]oct-8-yl)alkanols of the formula STR1 wherein Q is S or CH=CH; X is H, OH or another aromatic substituent; R is hydrogen, alkyl, alkenyl or alkynyl; Y and Y1 are taken together and are arylmethylene or aralkylmethylene (or a corresponding epoxy derivative) or Y and Y1 are taken separately and Y is hydrogen or OH, and Y1 is aryl, aralkyl, arylthio, or aryloxy; and structurally related 2-(piperidino)alkanols; pharmaceutical compositions thereof; methods of treating CNS disorders therewith; and intermediates useful in the preparation of said compounds.
- -
-
-