- Multifunctional agents based on benzoxazolone as promising therapeutic drugs for diabetic nephropathy
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Diabetic nephropathy (DN) is resulted from activations of polyol pathway and oxidative stress by abnormal metabolism of glucose, and no specific medication is available. We designed a novel class of benzoxazolone derivatives, and a number of individuals were found to have significant antioxidant activity and inhibition of aldose reductase of the key enzyme in the polyol pathway. The outstanding compound (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid was identified to reduce urinary proteins in diabetic mice suggesting an alleviation in the diabetic nephropathy, and this was confirmed by kidney hematoxylin-eosin staining. Further investigations showed blood glucose normalization, declined in the polyol pathway and lipid peroxides, and raised glutathione and superoxide dismutase activity. Thus, we suggest a therapeutic function of the compound for DN which could be attributed to the combination of hypoglycemic, aldose reductase inhibition and antioxidant.
- Zhang, Xin,Chen, Huan,Lei, Yanqi,Zhang, Xiaonan,Xu, Long,Liu, Wenchao,Fan, Zhenya,Ma, Zequn,Yin, Zhechang,Li, Lingyun,Zhu, Changjin,Ma, Bing
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Read Online
- Identification of a novel benzoxazolone derivative as a selective, orally active 18 kDa translocator protein (TSPO) ligand
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Optimization of the pharmacokinetic properties for a series of benzoxazolone derivatives led to the identification of 9b, which showed anxiolytic effect in a rat model. However, 9b, like known benzodiazepines, induced motor impairment. Investigation into
- Fukaya, Takayuki,Ishiyama, Takeo,Baba, Satoko,Masumoto, Shuji
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Read Online
- Design, synthesis and biological evaluation of methyl-2-(2-(5-bromo benzoxazolone)acetamido)-3-(1H-indol-3-yl)propanoate: TSPO ligand for SPECT
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The translator protein (TSPO, 18 kDa), a transmembrane mitochondrial protein, has been explored as an important biomarker by researchers because of its involvement in inflammation, immune modulation and cell proliferation. Recently, our group has explored a modified benzoxazolone derivative for diagnostic applications that has overcome few problems of first and second generation TSPO PET ligands. In this study, a new skeleton acetamidobenzoxazolone-indole, a conjugation of two TSPO pharmacophoric moieties benzoxazolone and indole, has been designed, synthesized and evaluated for TSPO targeting for SPECT. The methyl-2-(2-(5-bromo benzoxazolone)acetamido)-3-(1H-indol-3-yl)propanoate (MBIP) ligand was designed on the basis of pharmacophore modeling done on benzoxazolone based TSPO ligands which was then validated computationally for TSPO binding through docking studies (PDB ID: 4RYO, 4RYQ, and 4UC1) which showed a comparable Glide Gscore as compared to known ligands like PK11195, PBR28, and FGIN-127. MBIP was synthesized by amidation reaction of 2-(5-bromo-benzoxazolone)acetic acid with tryptophan methyl ester hydrochloride (yield 62%). The compound was synthesized and characterized using spectroscopic techniques like 1H-NMR, 13C-NMR, and mass spectroscopy. Purification was carried out by column chromatography and analytical HPLC (purity > 97%). The purified compound was labelled with 99mTc (radiochemical yield > 96%). The radiolabelled compound showed >94% stability in solution and >91% stability in serum after 24 h indicating the stable nature of the radio complex. A biodistribution study on BALB/c mice showed uptake of 99mTc-MBIP in TSPO rich organs and appropriate pharmacokinetics of excretion and release for a SPECT agent. Further evaluation of the 99mTc-MBIP may prove it as a potential candidate for TSPO targeting using SPECT.
- Srivastava, Pooja,Kaul, Ankur,Ojha, Himanshu,Kumar, Pravir,Tiwari, Anjani K.
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p. 114491 - 114499
(2016)
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Read Online
- Method for preparing carbonyl heterocyclic compound
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The invention provides a method for preparing a carbonyl heterocyclic compound, wherein Lewis base and hydrosilane are used as accelerators and can efficiently enable an ortho-substituted aniline compound to react with normal-pressure CO2 to generate corresponding carbonyl heterocyclic compounds containing different functional groups under mild conditions (100 DEG C, digital). According to the method, normal-pressure CO2 is used as an environmentally-friendly non-toxic carbonylation reagent, and cheap Lewis base and PMHS (industrial silicon waste) are used as accelerators, so that the use of CO, high-pressure CO2 and noble metal catalysts is avoided, the intermediate isocyanate does not need to be purified and separated, the pure product can be obtained only through simple suction filtration and separation after the reaction is finished, and the synthetic method is efficient and universal, is suitable for preparing a series of benzimidazolone, benzoxazolone and benzothiazolone compounds and has high industrial application value.
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Paragraph 0036-0040; 0114-0119
(2020/03/25)
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- Design, Synthesis, and In Silico Evaluation of Methyl 2-(2-(5-Bromo/chloro-2-oxobenzoxazol-3(2H)-yl)-acetamido)-3-phenylpropanoate for TSPO Targeting
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The high expression of the translocator protein (TSPO) makes it an ideal target for imaging and therapy. The present study is aimed at optimizing acetamidobenzoxazolone-based TSPO ligands by structural modification to overcome the limitations of TSPO ligands of the first two generations such as nonspecificity and polymorphism. Three different TSPO proteins, 2MGY, 4RYQ, and 4UC1, in the native and mutated form were chosen. Acetamidobenzoxazolones modified with phenylalanine methyl ester (methyl 2-(2-(5-bromo/chloro-2-oxobenzooxazol-3(2H)-yl)acetamido)-3-phenylpropanoate, ABPO-Br, ABPO-Cl) through better or comparable docking scores than the known TSPO ligands such as MBMP, FEBMP, FPBMP, and PK11195 are identified as potential TSPO ligands. ABPO-Cl and ABPO-Br were synthesized using phenylalanine methyl ester as a moiety for incorporation of the desired pharmacophoric feature. All the intermediates and final compounds were purified using column chromatography and analytical HPLC (purity > 97%). The purified compounds were characterized by 1H, 13C NMR and mass spectroscopy. Drug likeliness and comparative bioactivity analysis were performed using QikProp through prediction of various properties. Both analogs follow all the five Lipinski rules and three Jogersen’s rules predicting their drug likeliness. The other important aspects related to TSPO ligands such as blood-brain barrier penetration and better contrast have been predicted through lipophilicity (QP log P = 2.76 and 2.74 for ABPO-Br and ABPO-Cl, respectively) and serum binding (QP log Khsa = ?0.18 and ?0.25 for ABPO-Br and ABPO-Cl, respectively). The selectivity and distribution of these TSPO ligands were confirmed by 99mTc-ABPO-Br dynamic image in New Zealand rabbit. These results have shown that the ABPO analogs have the potential to act as better ligands as compared to known acetamidobenzoxazolone derivatives and would be of interest as a promising starting point for designing compounds for TSPO targeting.
- Kumar, P.,Srivastava, P.,Tiwari, Anjani Kumar
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p. 107 - 118
(2020/04/02)
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- AMINO PYRIMIDINE COMPOUND FOR INHIBITING PROTEIN TYROSINE KINASE ACTIVITY
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An amino pyrimidine compound for inhibiting protein tyrosine kinase activity, a pharmaceutical composition thereof, preparation therefor, and an application thereof. Specifically, an amino pyrimidine compound represented by formula (I), R1, R2, L, Y, R6, W, A, m, and n being defined in the specification, and a pharmaceutically acceptable salt, a stereoisomer, a solvent compound, a hydrate, a polymorphism, a prodrug, or an isotope variant thereof. The compound can be used for treating and/or preventing protein tyrosine kinase-related diseases such as cell proliferative diseases, cancers, and immune diseases.
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Paragraph 0350; 0351
(2019/06/07)
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- Comparative evaluation of 99mTc-MBIP-X/11[C] MBMP for visualization of 18 kDa translocator protein
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An elevated translocator protein (18 kDa, TSPO) density is observed during inflammation in the brain and peripheral organs making it a viable target for imaging. Recently, our group has explored a pharmacophore skeleton acetamidobenzoxazolone for positron emission tomography (PET) and single photon emission computed tomography (SPECT) applications to target TSPO. 2-(2-(5-Bromo/chloro benzoxazolone)acetamide)-3-(1H-indol-3-yl)propionate (MBIP-Br/Cl) were synthesized by using tryptophan methyl ester and compared with 2-[5-(4-methoxyphenyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenyl acetamide (MBMP) through tracer techniques. Computational docking showed similar results for MBIP-Br/Cl in comparison to MBMP. Their ex vivo and in vivo biodistributions were assessed in TSPO-rich organs as well as their release kinetics 0-120 min post injection. The ex vivo biodistribution showed a 7 fold higher uptake (5.16%ID per g vs. 0.72%ID per g) in the heart and a 2.5 fold higher uptake (12.91%ID per g vs. 4.69%ID per g) in the lungs for 99mTc-MBIP-Cl compared to that of 99mTc-MBIP-Br at 15 min. These findings demonstrated that 99mTc-MBIP-Cl has improved pharmacokinetic properties compared to 99mTc-MBIP-Br for SPECT application and is comparable to [11C]MBMP.
- Srivastava, Pooja,Kumari, Neelam,Kakkar, Dipti,Kaul, Ankur,Kumar, Pravir,Tiwari, Anjani K.
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p. 11288 - 11295
(2019/07/22)
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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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- Visible-Light-Induced Intramolecular C(sp2)-H Amination and Aziridination of Azidoformates via a Triplet Nitrene Pathway
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Catalytic intramolecular C-H amination and aziridination reactions of o-allylphenyl azidoformates have been achieved under visible-light irradiation, providing a mild, clean, and efficient method for the synthesis of useful benzoxazolones and [5.1.0] bicyclic aziridines. Mechanistic studies suggest that a triplet nitrene acts as the reactive intermediate. The chemoselectivity of the reaction, with alkyl olefin aziridination ? electron deficient olefin aziridination ≈ C(sp2)-H amination ? C(sp3)-H amination was observed, which may be instructive in the development of an understanding of visible-light-induced triplet nitrene transformation reactions.
- Zhang, Yipin,Dong, Xunqing,Wu, Yanan,Li, Guigen,Lu, Hongjian
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p. 4838 - 4842
(2018/08/24)
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- COMPOUNDS AND THEIR METHODS OF USE
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The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including Dravet syndrome or epilepsy are also provided herein.
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Page/Page column 82, 83
(2018/09/08)
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- Rhodium(II)-Catalyzed Undirected and Selective C(sp2)-H Amination en Route to Benzoxazolones
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Rhodium(II) can effectively promote the activation and cyclization of arylcarbamate substrates to yield benzoxazolones via an intramolecular nitrene C-H insertion reaction. Investigation of the substrate scope shows that the reaction undergoes selective a
- Singh, Ritesh,Nagesh, Kommu,Parameshwar, Matam
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p. 6520 - 6524
(2016/10/14)
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- BENZOXAZINONE DERIVATIVES AND ANALOGUES THEREOF AS MODULATORS OF TNF ACTIVITY
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A series of substituted 3,4-dihydro-2H-.1,4-benzoxazin-3-one derivatives, and analogues thereof, being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune
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Page/Page column 61
(2016/12/26)
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- NOVEL BICYCLIC BROMODOMAIN INHIBITORS
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The invention relates to substituted bicyclic compounds, which are useful for inhibition of BET protein function by binding to bromodomains, pharmaceutical compositions comprising these compounds, and use of the compounds and compositions in therapy.
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Paragraph 0198
(2015/01/16)
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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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- Molecular iodine-mediated domino reaction for the synthesis of benzamides, 2,2-Diazidobenzofuran-3(2H)-ones and benzoxazolones
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A simple and efficient domino protocol has been developed for the preparation of biologically important benzamides, 2,2-diazidobenzofuran-3(2H)- ones and benzoxazolones from various structurally and electronically divergent acetophenones and ortho-hydroxyacetophenones in the presence of molecular iodine, sodium azide and sodium bicarbonate at 100 °C in good to excellent yields. Copyright
- Rajendar,Kant, Ruchir,Narender
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supporting information
p. 3591 - 3596
(2014/01/06)
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- Convenient synthesis of benzoxazolone derivatives by cross-coupling of benzoxazolone boronates with aryl halides
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Benzoxazolone derivatives with various substituents at the C-5 position were synthesized efficiently via benzoxazolone boronates as the key intermediate. The target compounds were also synthesized from (het)aryl halides in a one-pot process. These methods permitted efficient exploratory syntheses of a series of benzoxazolone derivatives. Georg Thieme Verlag Stuttgart New York.
- Fukaya, Takayuki,Masumoto, Shuji
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p. 3269 - 3275
(2013/12/04)
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- BIARYL ETHER SULFONAMIDES AND THEIR USE AS THERAPEUTIC AGENTS
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This invention is directed to biaryl ether sulfonamides, or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment and/or prevention of sodium channel-mediated diseases or conditions, such as pain.
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Page/Page column 125
(2013/05/22)
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- Design, synthesis and structure-activity relationships of novel benzoxazolone derivatives as 18 kDa translocator protein (TSPO) ligands
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Selective 18 kDa translocator protein (TSPO) ligands are expected to be therapeutic agents with a wide spectrum of action on psychiatric disorders and fewer side effects. We designed novel benzoxazolone derivatives and examined the structure-activity rela
- Fukaya, Takayuki,Kodo, Toru,Ishiyama, Takeo,Kakuyama, Hiroyoshi,Nishikawa, Hiroyuki,Baba, Satoko,Masumoto, Shuji
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p. 5568 - 5582
(2012/10/29)
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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 HETEROCYCLIC COMPOUND
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A drug having a high affinity for benzodiazepine ω3 receptors and showing curative and preventive effects for anxiety and depression, which comprises as the active ingredient, for example, a compound of the formula (1): wherein R1 an
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Page/Page column 26
(2010/11/24)
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