- Synthesis and evaluation of technetium-99m labelled 1-(2-methoxyphenyl)piperazine derivative for single photon emission computed tomography imaging for targeting 5-HT1A
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Quantitative changes in expression level of 5HT1A are somewhere related to common neurological disorders such as anxiety, major depression and schizophrenia. We have designed EDTA conjugated SPECT imaging probe for localization of 5HT1A/s
- Kumari, Neelam,Kaul, Ankur,Varshney, Raunak,Singh, Vinay Kumar,Srivastava, Krishna,Bhagat, Sunita,Mishra, Anil Kumar,Tiwari, Anjani Kumar
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Read Online
- [99mTc-BBPA]: A possible SPECT agent to understand the role of 18-kDa translocator protein (PBR/TSPO) during neuro-glial interaction
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The translocator protein (TSPO, 18 kDa) is one of the most promising biomarker to understand the role of neuroinflammation in human as well as in different animal species. Here we report a new TSPO-selective ligand 2-(5-(2-(bis(pyridin-2-yl methyl)amino)acetamido)-2-oxobenzo[d] oxazol-3(2H)-yl)-N-methyl-N-phenylacetamide, BBPA, which is supposed to be a potential probe to understand the role of TSPO in neuro-glial interaction through SPECT modality.
- Bhagat, Sunita,Deepika,Kaul, Ankur,KumarTiwari, Anjani,Kumari, Neelam,Mishra, Gauri,Singh, Vinay Kumar,Srivastava, Krishna
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supporting information
(2022/02/17)
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- Identification and characterization of benzo[d]oxazol-2(3H)-one derivatives as the first potent and selective small-molecule inhibitors of chromodomain protein CDYL
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Chemical probes of epigenetic ‘readers’ of histone post-translational modifications (PTMs) have become powerful tools for mechanistic and functional studies of their target proteins in physiology and pathology. However, only limited ‘reader’ probes have been developed, which restricted our understanding towards these macromolecules and their roles in cells or animals. Here, we reported a structure-guided approach to develop and characterize benzo [d]oxazol-2(3H)-one analogs as the first potent and selective small-molecule inhibitors of chromodomain Y-like (CDYL), a histone methyllysine reader protein. The binding conformation between the chromodomain of CDYL and the modified peptidomimetics was studied via molecular docking and dynamic simulations, facilitating subsequent virtual screening of tens of hits from Specs chemical library validated by SPR technique (KD values: from 271.1 μM to 5.4 μM). Further design and synthesis of 43 compounds helped to interpret the structure-activity relationship (SAR) that lead to the discovery of novel small-molecule inhibitors of CDYL. Compound D03 (KD: 0.5 μM) was discovered and showed excellent selectivity among other chromodomain proteins, including CDYL2 (>140 folds), CDY1 (no observed binding) and CBX7 (>32 folds). Moreover, we demonstrated that D03 engaged with endogenous CDYL in a dose-dependent manner, and perturbed the recruitment of CDYL onto chromatin, resulting in transcriptional derepression of its target genes. Finally, the results showed that D03 promoted the development and branching of neurodendrites by inhibiting CDYL in hippocampal and cortical cultured neurons. This study not only discovers the first selective small-molecule inhibitors of CDYL, but provids a new chemical tool to intervene the dynamic nature of bio-macromolecules involved in epigenetic mechanism.
- Yang, Lixin,Liu, Yongqing,Fan, Minghua,Zhu, Guiwang,Jin, Hongwei,Liang, Jing,Liu, Zhenming,Huang, Zhuo,Zhang, Liangren
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- Concise and Additive-Free Click Reactions between Amines and CF3SO3CF3
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Trifluoromethyl trifluoromethanesulfonate has proved to be an excellent reservoir of difluorophosgene and a promising click ligation for amines in the preparation of urea derivatives, heterocycles, and carbamoyl fluorides under metal- and additive-free conditions. The reactions are rapid, efficient, selective, and versatile, and can be performed in benign solvents, giving products in excellent yields with minimal efforts for purification. The characteristics of the reactions meet the requirements of a click reaction. The use of trifluoromethyl trifluoromethanesulfonate as a click reagent is advantageous over other “CO” sources (e.g., TsOCF3, PhCO2CF3, CsOCF3, AgOCF3, and triphosgene) because this reagent is readily accessible; easy to scale up; and highly reactive, even under metal- and additive-free conditions. It is anticipated that CF3SO3CF3 will be increasingly as important as SO2F2 as a click agent in future drug design and development.
- Song, Hai-Xia,Han, Zhou-Zhou,Zhang, Cheng-Pan
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supporting information
p. 10907 - 10912
(2019/08/02)
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- SUBSTITUTED BICYCLE HETEROCYCLIC DERIVATIVES USEFUL AS ROMK CHANNEL INHIBITORS
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Disclosed are compounds of Formula (I) or a salt thereof, wherein R1 is (II) or (III); each W is independently NR1b or O; Z is a bond or CHR1d; and R1, R2, Rd, R3, L1, L2, R1a, R1b, R1c, and n are define herein. Also disclosed are methods of using such compounds as inhibitors of ROMK, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating cardiovascular diseases.
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Page/Page column 112
(2018/06/06)
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- SUBSTITUTED NITROGEN CONTAINING COMPOUNDS
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Disclosed are compounds of Formula (I): or a salt thereof, Formula (II) wherein R1 is: or; each W is independently NR1b or O; Z is a bond or CHR1d; and R1, R2, Rd, R3a, R3b, L1, B, V, Y, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of ROMK, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating cardiovascular diseases.
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Page/Page column 90
(2019/01/05)
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- Modified benzoxazolone derivative as 18-kDa TSPO ligand
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We have synthesized six new congeners of acetamidobenzoxazolone for Translocator Protein [18 kDa, TSPO] imaging. The best in vitro binding affinity (10.8?±?1.2?nm) for TSPO was found for N-methyl-2-(5-(naphthalen-1-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)-N-phen
- Kumari, Neelam,Chadha, Nidhi,Srivastava, Pooja,Mishra, Lokesh Chandra,Bhagat, Sunita,Mishra, Anil K.,Tiwari, Anjani K.
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p. 511 - 519
(2017/09/13)
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- Discovery of potent IDO1 inhibitors derived from tryptophan using scaffold-hopping and structure-based design approaches
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Indoleamine 2,3-dioxygenase 1 (IDO1) is frequently hijacked by tumors to escape the host immune response, and the enzyme is now firmly established as an attractive target for cancer immunotherapy. To identify novel IDO1 inhibitors suitable for drug development, a scaffold-hopping strategy combined with the average electrostatic potentials calculation was ultilized to design novel benzoxazolinone derivatives. Among these, compounds 7e, 7f and 9c exhibited the inhibitory potency in the low micromolar range and displayed negligible level of cytotoxicity against HeLa cells. Treatment with these three compounds promoted the proliferation of T lymphocyte and led to the dramatic decrease of regulatory T cells in the B16F1 cells and na?ve T cells co-culture system. Subsequent spectroscopic experiments suggested that these benzoxazolinones formed a coordinate bond with the heme iron to stabilize the complex. This study suggested that the benzoxazolinone was an interesting scaffold for discovering novel IDO1 inhibitors, and these compounds are attractive candidates for further development.
- Zou, Yi,Wang, Yan,Wang, Fang,Luo, Minghao,Li, Yuezhen,Liu, Wen,Huang, Zhangjian,Zhang, Yihua,Guo, Wenjie,Xu, Qiang,Lai, Yisheng
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p. 199 - 211
(2017/07/03)
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- INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION
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Compounds of Formulas I-VI, including pharmaceutically acceptable salts thereof, and compositions and methods for treating human immunodeficiency virus (HIV) infection are set forth. Formula I is exemplified below: Formula (i)
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Page/Page column 97
(2016/11/17)
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- Facile Synthesis of Benzo[ d ]azol-2(3 H)-ones Using 2-Phenoxycarbonyl-4,5-dichloropyridazin-3(2 H)-one as Green CO Source
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Developing eco-friendly, stable, and easy-to-handle acyl sources is of great importance in synthetic and green chemistry. This study describes the synthesis of benzo[d]azol-2(3H)-ones such as benzo[d]thiazol-2(3H)-ones, benzo[d]oxazol-2(3H)-ones, and benzo[d]imidazol-2(3H)-ones using 2-phenoxycarbonyl-4,5-dichloropyridazin-3(2H)-one in one pot. The reaction reported is carried out under neutral or acidic conditions in the presence of zinc or sodium bicarbonate to give the corresponding heterocycles in good to excellent yields. The reaction uses a solid stable carbonyl source that is a recyclable functional-group carrier, pyridazin-3(2H)-one.
- Ryu, Ki Eun,Kim, Bo Ram,Sung, Gi Hyeon,Yoon, Hyo Jae,Yoon, Yong-Jin
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supporting information
p. 1985 - 1990
(2015/09/01)
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- BENZOXAZOLONE DERIVATIVES AS ACID CERAMIDASE INHIBITORS, AND THEIR USE AS MEDICAMENTS
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The present invention relates to benzoxazolone derivatives as acid ceramidase inhibitors, pharmaceutical compositions containing these inhibitors and methods of inhibiting acid ceramidase for the treatment of disorders in which modulation of the levels of ceramide is clinically relevant. The invention also provides benzoxazolone derivatives for use as a medicament in the treatment of cancer, inflammation, pain, inflammatory pain or pulmonary diseases.
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Page/Page column 40; 42; 43
(2015/12/11)
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- Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure-Activity Relationship (SAR) Studies
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Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We examined a diverse series of substitutions on both benzoxazolone ring and carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity-stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic administration. The results expand our arsenal of AC inhibitors, thereby facilitating the use of these compounds as pharmacological tools and their potential development as drug leads.
- Bach, Anders,Pizzirani, Daniela,Realini, Natalia,Vozella, Valentina,Russo, Debora,Penna, Ilaria,Melzig, Laurin,Scarpelli, Rita,Piomelli, Daniele
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supporting information
p. 9258 - 9272
(2015/12/23)
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- Pyrrole inhibitors of S-nitrosoglutathione reductase as therapeutic agents
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The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.
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Page/Page column 312
(2015/11/16)
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- Heterocyclic acyl-phosphate bioisostere-based inhibitors of Staphylococcus aureus biotin protein ligase
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Inhibitors of Staphylococcus aureus biotin protein ligase (SaBPL) are generated by replacing the acyl phosphate group of biotinyl-5′-AMP with either a 1,2,3-triazole (see 5/10a/10b) or a 1,2,4-oxadiazole (see 7) bioisostere. Importantly, the inhibitors are inactive against the human BPL. The nature of the 5-substituent in the component benzoxazolone of the optimum 1,2,3-triazole series is critical to activity, where this group binds in the ATP binding pocket of the enzyme.
- Tieu, William,Jarrad, Angie M.,Paparella, Ashleigh S.,Keeling, Kelly A.,Soares Da Costa, Tatiana P.,Wallace, John C.,Booker, Grant W.,Polyak, Steven W.,Abell, Andrew D.
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supporting information
p. 4689 - 4693
(2015/01/09)
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- General and efficient synthesis of benzoxazol-2(3H)-ones: Evolution of their anti-cancer and anti-mycobacterial activities
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A novel class of benzo[d]oxazol-2(3H)-one derivatives has been synthesized and their in vitro cytotoxicity against human pancreatic adenocarcinoma and human non-small cell lung carcinoma cancer cell lines was evaluated. Many of these compounds were found to display excellent to moderate activity. Among them, 6b, 6l, 6n and 6x were identified as lead molecules. In particular, 6l and 6n were found to be potent against the pancreatic adenocarcinoma cell line whereas the 6x was found to be effective against the human non-small cell lung carcinoma cell line. Conversely, the compounds 6l-x were found to be ineffective against Mycobacterium tuberculosis. Of the various molecules, 6h showed promising anti-mycobacterial activity, with an IC50 value equal to that of ciprofloxacin.
- Indrasena Reddy,Aruna,Sudhakar Babu,Vijayakumar,Manisha,Padma Sridevi,Yogeeswari,Sriram
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p. 59594 - 59602
(2015/02/19)
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- 2, 4 -DIAMINOPYRIMIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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The present invention relates to novel pyrimide derivatives of formula (I): that are useful as kinase inhibitors. More particularly, the present invention relates to novel pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders.
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Page/Page column 165
(2012/05/20)
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- 2,3-DIARYL- OR HETEROARYL-SUBSTITUTED 1,1,1-TRIFLUORO-2-HYDROXYPROPYL COMPOUNDS
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The present invention relates to compounds of formula I wherein R1a to R1c, R2, R3 and R5 are as defined in the description and claims and R4 signifies a bicyclic heteroaryl group or a cyanophenyl group, as well as pharmaceutically acceptable salts thereof. The compounds are glucocorticoid receptor antagonists useful for the treatment and/or prevention of diseases such as diabetes, dyslipidemia, obesity, hypertension, cardiovascular diseases, adrenal imbalance or depression.
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Page/Page column 63-64
(2010/10/19)
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- Synthesis of benz[d]oxazolones involving concomitant acetyl migration from oxygen to nitrogen
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Heating of o-acetoxybenzoyl azides 6-10 in toluene leads to the Curtius reaction, which, when followed by closure of oxazolone ring with concomitant migration of acetyl group from oxygen to nitrogen, produces 3-acetoxybenz[d] oxazol-2(3H)-ones 11-15, which undergo hydrolysis with hot dilute hydrochloric acid to furnish benz[d]oxazol-2(3H)-ones 17-21. Thermal reaction of 2-hydroxy-5-nitrobenzoyl azide (22) in toluene finally yields a mixture of 5-nitrobenz[d]oxazol-2(3H)-one (20) and 5-nitrobenz[d]isoxazol-3(2H)-one (23). Copyright Taylor & Francis Group, LLC.
- Ray, Sibdas,Ghosh, Sukla
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experimental part
p. 2377 - 2388
(2010/09/07)
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- NOVEL PIPERAZINE DERIVATIVES AS INHIBITORS OF STEAROYL-CoA DESATURASE
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The present invention relates to piperazine derivatives that act as inhibitors of stearoyl-CoA desaturase. The invention also relates to methods of preparing the compounds, compositions containing the compounds, and to methods of treatment using the compounds.
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Page/Page column 23
(2009/10/01)
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- Synthesis of benzoxazole-2-ones, benzothiazole-2-ones and their 2-thione derivatives: Efficient conversion of 2-thione to 2-oxo derivatives
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A highly practical procedure for preparing benzoxazole-2-ones, benzothiazole-2-ones and its 2-thione derivatives using ethylchloroformate and carbon disulfide and the corresponding aminophenols and aminothiophenols as the starting materials in one-pot protocol is presented. The yields vary from good to excellent, the conditions are mild, and the use of toxic and harmful chemicals is avoided. An efficient conversion of benzoxazole-2-thione to 2-one derivative in high yield has also been carried out.
- Singh,Singh, Pallavi,Singh, Shweta
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p. 1666 - 1671
(2008/09/19)
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- Alpha2C adrenoreceptor agonists
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In its many embodiments, the present invention relates to a novel class of phenylmorpholine and phenylthiomorpholine compounds useful as α2C adrenergic receptor agonists, pharmaceutical compositions containing the compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the α2C adrenergic receptor agonists using such compounds or pharmaceutical compositions.
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Page/Page column 37-38
(2010/11/26)
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- Benzoxazoline and benzimidazoline derivatives as novel aldose reductase inhibitors, part 2: Lead optimization
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We designed novel aldose reductase inhibitors, benzoxazoline and benzimidazoline derivatives, based on lead evolution from spiroquinazolinones. In order to optimize in vivo activity in the lens, variously substituted derivatives were synthesized. The relationship between structure and in vitro activity was also analyzed by comparative molecular field analysis. The optimized compound exhibited high potency in the lens.
- Nakao, Kazuya,Asao, Masaaki,Shirai, Hiroki,Saito, Kiyoshi,Moriya, Tamon,Iwata, Hiroshi,Matsumoto, Mamoru,Matsuoka, Yuzo,Shimizu, Ryo
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p. 631 - 642
(2007/10/03)
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- The vicarious nucleophilic substitution of hydrogen and related reactions in nitrobenzoxazoles
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5- and 6-nitrobenzoxazoles 3 and 4 react with nucleophiles exclusively at C-2, giving ring opening products. If position 2- is blocked with phenyl substituent the reaction takes place in the carbocyclic ring affording the VNS products. 2-Methylthio-5-nitrobenzoxazole 7 and its 6-nitro isomer 8 give products which result from addition of a nucleophile to the carbocyclic ring (VNS) as well as to the heterocyclic ring (S(N)Ar and ring cleavage). 2-Methylthiobenzoxazoles can be readily converted to the corresponding benzoxazolones via oxidative hydrolysis.
- Makosza, Mieczyslaw,Stalewski, Jacek
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p. 7277 - 7286
(2007/10/02)
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- Benzimidazole derivatives, their preparation and use
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A compound having the formula STR1 wherein R 1 is hydrogen, NH 2 or C 1-6 -alkyl which may be branched;X is O, S, NCN;Y is O, S;R 4, R 5, R 6 and R 7 independently of each other are hydrogen, halogen, CF 3, NO 2, NH 2, OH, C 1-6 -alkoxy, C( O)-phenyl or SO 2 NR I R II wherein R I and R II independently are hydrogen or C 1-6 -alkyl;R 11 is hydrogen, halogen, NO 2 or SO 2 NR''R"" wherein R'' and R"" independently are hydrogen or C 1-6 -alkyl;R 13 is hydrogen, halogen, phenyl, CF 3, NO 2 ;R 12 is hydrogen or together with R 13 forms a C 4-7 -carbocyclic ring which may be aromatic or partially saturated;R 14 is hydrogen or together with R 13 forms a C 4-7 -carbocyclic ring which may be aromatic or partially saturated;pharmaceutical compositions thereof,and a method of treating a disease in a mammal, including a human, responsive to opening of potassium channels, which comprises administering to a mammal in need thereof an effective amount of a compound as first above indicated, are disclosed.
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- A Simple Synthesis of 2(3H)-Benzoxazolones using Phenyl Chloroformate
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2(3H)-Benzoxazolones 3 can be prepared directly from the corresponding 2-aminophenols and phenyl chloroformate.The intermediate 2-hydroxy phenylcarbamates 2 are formed easily in aqueous alcohol solvent and these are converted rapidly to product, without their isolation, using one equivalent of sodium hydroxide.The synthesis accommodates a wide variety of substituents, including the easily hydrolyzed ethyl ester.
- Maleski, Robert J.,Osborne, C. Edward,Cline, Sharon M.
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p. 1937 - 1939
(2007/10/02)
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- PREPARATION OF CYCLIC CARBONATES AND 2-OXAZOLIDONES USING DI-2-PYRIDYL CARBONATE
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Cyclic carbonates and 2-oxazolidones are conveniently prepared in high yields by the reaction of diols and β-amino alcohols with di-2-pyridyl carbonate.It is of synthetic significance that the formation of cyclic carbonates in refluxing toluene occurs under essentially neutral conditions.
- Kim, Sunggak,Ko, Young Kwan
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p. 1625 - 1630
(2007/10/02)
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