- Synthesis, structural characterization, docking, lipophilicity and cytotoxicity of 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-alkyl carbamates, novel acetylcholinesterase and butyrylcholinesterase pseudo-irreversible inhibitors
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In the current study, sixteen novel derivatives of (R)-1-(6-fluorobenzo[d]thiazol-2-yl)ethanamine were synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. Chemical structures together with purity of the synthesized compounds were substantiated by IR, 1H, 13C, 19F NMR, high resolution mass spectrometry and elemental analysis. The optical activities were confirmed by optical rotation measurements. The synthesized compounds were evaluated for their AChE and BChE inhibitory activities. In addition, the cytotoxicity of the most active compounds was investigated against human cell lines employing XTT tetrazolium salt reduction assay and xCELLigence system allowing a label-free assessment of the cells proliferation. Our results demonstrated that the inhibitory mechanism was confirmed to be pseudo-irreversible, in line with previous studies on carbamates. Compounds indicated as 3b, 3d, 3l and 3n showed the best AChE inhibitory activity of all the evaluated compounds and were up to tenfold more potent than standard drug rivastigmine. The binding mode was determined using state-of-the-art covalent docking and scoring methodology. The obtained data clearly demonstrated that 3b, 3d, 3l and 3n benzothiazole carbamates possess high inhibitory activity against AChE and BChE and concurrently negligible cytotoxicity. In conclusion, our results indicate, that these derivatives could be promising in an effective therapeutic intervention for Alzheimer's disease.
- Pejchal, Vladimír,?těpánková, ?árka,Pejchalová, Marcela,Královec, Karel,Havelek, Radim,R??i?ková, Zdenka,Ajani, Haresh,Lo, Rabindranath,Lep?ík, Martin
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Read Online
- Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibition agents
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Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. Here we synthesized and evaluated sixteen new 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibitors. The optimal compound 9e exhibited excellent antiproliferative activity against non-small cell lung cancer NCI-H2228 cells, which is better than that of Brigatinib and similar to Ceritinib. Mechanism study revealed that the optimal compound 9e decreased the mitochondrial membrane potential and arrested NCI-H2228 cells in the G0/G1 phase, finally resulting in cellular apoptosis. It is interesting that 9e could effectively inhibit the migration of NCI-H2228 cells and may be a promising leading compound for chemotherapy of metastatic cancer.
- An, Baijiao,Chan, Albert S. C.,Fan, Yangyang,Li, Wei,Li, Xingshu,Wu, Feng,Yao, Han,Zhang, Niuniu
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supporting information
(2021/07/19)
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- AcOH-mediated aerobic oxidative synthesis of 2-thioalkylbenzothiazoles via a three-component reaction
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An AcOH-mediated three-component reaction of 2-aminothiophenols, α,β-unsaturated aldehydes, and thiophenols to prepare the high value-added 2-thioalkylbenzothiazoles was developed. The reaction was conducted under metal-free conditions, where oxygen served as the terminal oxidant. In addition, this strategy is tolerant of kinds of functional groups, providing efficient access to a variety of functionalized benzothiazole derivatives in moderate to good yields. What's more, this reaction has complete regioslectivity and provides a powerful method for building complex molecules.
- Li, Xiaowei,Li, Yuxiu,Liu, Ruihua,Wang, Zemin,Li, Xiangqian,Shi, Dayong
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supporting information
(2020/05/28)
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- COMPOUNDS FOR THE MODULATION OF MYC ACTIVITY
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The present invention provides novel compounds of Formula (I) and Formula (II) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases, e.g., cancers (e.g., breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer), benign neoplasms, angio genesis, inflammatory diseases, fibrosis (e.g., polycystic kidney disease), autoinflammatory diseases, and autoimmune diseases in a subject.
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Paragraph 822-823
(2017/01/31)
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- Synthesis, structural characterization, antimicrobial and antifungal activity of substituted 6-fluorobenzo[d]thiazole amides
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A series of novel 1-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-3-substituted phenyl amides was synthesized by the condensation reaction of (1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethanamine with substituted benzoyl chlorides under mild conditions. Their structures were confirmed by 1H NMR, 13C NMR and 19F NMR spectra, elemental analyses and in three cases also by single-crystal X-ray diffraction techniques. The optical activities were confirmed by optical rotation measurements. All the synthesized compounds were screened for antibacterial and antifungal activity against a variety of bacterial and fungal strains. Some of the compounds reveal antibacterial and antifungal activity comparable or slightly better to that of chloramphenicol, cefoperazone and amphotericin B used as medicinal standards.
- Pejchal, Vladimír,Pejchalová, Marcela,R??i?ková, Zdeňka
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p. 3660 - 3670
(2015/09/07)
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- Synthesis, characterization and in vitro antimicrobial assessment of some novel 4H-1, 4-benzothiazines and their sulfone derivatives
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In recent years, synthesis and biological evaluation of novel 4H-1,4-benzothiazines and their sulfone derivatives have gained momentum due to their medicinal and industrial importance. Our studies focused on the design and synthesis of new antimicrobial agents, and for this purpose a series of novel 4H-1,4-benzothiazines and their sulfone derivatives were synthesized and their in vitro antimicrobial assessment was carried out against a representative panel of Gram-positive and Gram-negative bacteria strains and selected fungi species. The reported 4H-1,4-benzothiazines were prepared by condensation followed by oxidative cyclization of substituted 2-aminobenzenethiols with compounds containing active methylene groups. It is believed that the reaction proceeds via intermediary of the enaminoketone system. The sulfone derivatives were synthesized by oxidation of 4H-1,4-benzothiazines using 30% hydrogen peroxide in glacial acetic acid. Structure determination was done by spectral and elemental investigations.
- Gautam, Naveen,Bishnoi, Ajay Kumar,Guleria, Anjali,Jangid, Dinesh Kumar,Gupta, Sudesh Kumar,Gautam, Dinesh Chand
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- Fluorescence properties of 5-(5,6-dimethoxybenzothiazol-2-yl)-2′- deoxyuridine (dbtU) and oligodeoxyribonucleotides containing d btU
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We describe the synthesis and photophysical properties of 11 substituted 5-(benzothiazol-2-yl)-2′-deoxyuridine derivatives and oligodeoxyribonucleotides (ODNs) containing 5-(5,6-dimethoxybenzothiazol-2-yl)- 2′-deoxyuridine (dbtU), which was the strongest fluorescent derivative among those prepared. The fluorescence properties of dbtU itself and ODNs containing dbtU show the same tendency of being weaker in both neutral and acidic solution and stronger in basic solution. The ODNs (15mer) containing 16 combinations of 5′-XbtU-3′ and 5′-btUY-3′, where X, Y = A, T, G, or C, were synthesized, and their fluorescence intensity and quantum yield in basic solution were compared. On average, only the ODN with the 5′-G btU-3′ sequence shows a 7.9-fold lower fluorescence intensity than the other sequences. Ab initio calculations of 5′-G btU-3′ and 5′-btUG-3′ as models under basic conditions suggest that the lower fluorescence of the ODN containing the 5′-GbtU-3′ sequence is caused by a wider overlap between stacked guanine (Gua) and btUra than that of the 5′- btUG-3′ sequence and that the HOMO is delocalized not only on btUra but also on Gua.
- Hirose, Wataru,Sato, Kousuke,Matsuda, Akira
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experimental part
p. 6206 - 6217
(2011/12/02)
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- NOVEL COMPOUNDS
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The invention relates to tricyclic derivatives, and their use in treating diseases and conditions mediated by antagonism of the mGluR5 receptor, in particular substance related disorders. In addition, the invention relates to compositions containing the derivatives and processes for their preparation.
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Page/Page column 54
(2011/12/14)
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- Syntheses and evaluation of fluorinated benzothiazole anilines as potential tracers for β-amyloid plaques in Alzheimer's disease
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[11C]2-(4′-(Methylamino)phenyl)-6-hydroxybenzothiazole ([11C]PIB) is a most potential PET tracer for detecting the β-amyloid plaques in Alzheimer's disease. Here the syntheses of three fluorinated PIB, namely 2-(4′-(methylamino)phenyl)-6-fluoroethoxybenzothiazole (O-FEt-PIB), 2-(4′-(methylamino)phenyl)-6-fluoro-benzothiazole (F-N-Me) and 2-(4′-(dimethylamino)phenyl)-6-fluorobenzo-thiazole (F-N,N-Me), and the radiosynthesis of one corresponding 18F-labeled PIB compound, [18F]O-FEt-PIB, as well as their in vitro/in vivo biological characters were reported. The structures of the products were confirmed by IR, 1H NMR, EI/ESI-MS, elemental analysis and HRMS techniques. The radiolabeled product was characterized by radio-TLC and radio-HPLC and purified by semi-preparative radio-HPLC. The suitable biological characters showed these tracers were potential to be developed as probes for detecting β-amyloid plaques in Alzheimer's disease.
- Zheng, Ming-Qiang,Yin, Duan-Zhi,Qiao, Jin-Ping,Zhang, Lan,Wang, Yong-Xian
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p. 210 - 216
(2008/09/17)
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- Identification of a novel series of tetrahydrodibenzazocines as inhibitors of 17β-hydroxysteroid dehydrogenase type 3
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A novel series of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) inhibitors has been identified. These inhibitors, based on a dibenzazocine core, exhibited picomolar to low nanomolar inhibition of 17β-HSD3 in cell-free enzymatic as well as in cell-based transcriptional reporter assays.
- Fink, Brian E.,Gavai, Ashvinikumar V.,Tokarski, John S.,Goyal, Bindu,Misra, Raj,Xiao, Hai-Yun,Kimball, S. David,Han, Wen-Ching,Norris, Derek,Spires, Thomas E.,You, Dan,Gottardis, Marco M.,Lorenzi, Matthew V.,Vite, Gregory D.
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p. 1532 - 1536
(2007/10/03)
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- Synthesis of 7-chloro-5-trifluoromethyl/7-fluoro/7-trifluoromethyl-4H-1,4-benzothiazines as antimicrobial agents
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7-Chloro-5-trifluoromethyl/7-fluoro/7-trifluoromethyl-4H-1,4-benzothiazines have been synthesized by 2-amino-5-fluoro/5-trifluoromethyl/5-chloro-3-trifluoromethyl benzenethiols condensed with β-diketone/β-ketoesters in the presence of DMSO involving oxidative cyclization. Pharmacological activities have also been included.
- Rathore, Bhawani Singh,Kumar
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p. 5678 - 5682
(2007/10/03)
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- Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications
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Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat, 9) inhibits aldose reductase with an IC50 of 5 nM, while being 5400 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. It lowers nerve and lens sorbitol levels with ED50's of 1.9 and 4.5 mg/kg/d po, respectively, in the 5-day STZ-induced diabetic rat model. In a 3-month diabetic intervention model (1 month of diabetes followed by 2 months of drug treatment at 5 mg/kg/d po), it normalizes polyols and reduces the motor nerve conduction velocity deficit by 59% relative to diabetic controls. It has a favorable pharmacokinetic profile (F, 82%; t1/2, 5.6 h; Vd, 0.694 L/kg) with good drug penetration in target tissues (Cmax in sciatic nerve and eye are 2.36 and 1.45 μg equiv/g, respectively, when dosed with [14C] lidorestat at 10 mg/kg po).
- Van Zandt, Michael C.,Jones, Michael L.,Gunn, David E.,Geraci, Leo S.,Jones, J. Howard,Sawicki, Diane R.,Sredy, Janet,Jacot, Jorge L.,DiCioccio, A. Thomas,Petrova, Tatiana,Mitschler, Andre,Podjarny, Alberto D.
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p. 3141 - 3152
(2007/10/03)
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- Imidazoline derivatives as alpha-1A adrenoceptor ligands
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Compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof are disclosed. Such compounds are useful in the treatment of Alpha-1A mediated diseases or conditions such as urinary incontinence.
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Page/Page column 12-13
(2010/02/11)
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- Color tunable phosphorescent light-emitting diodes based on iridium complexes with substituted 2-phenylbenzothiozoles as the cyclometalated ligands
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Several iridium complexes {iridium(III)bis[2-(3-methoxyphenyl)-1,3- benzothiozolato-N,C2′] acetylacetonate (MeO-BT) 2Ir(acac), iridium(III)bis[2-(2,4-difluorophenyl)-1,3- benzothiozolato-N,C2′] acetylacetonate (2F-BT) 2Ir(acac), and iridium(III)bis[2-(2,4-difluorophenyl)-6-fluoro-1,3- benzothiozolato-N,C2′] acetylacetonate (3F-BT) 2Ir(acac)} having different substituents on 2-phenylbenzothiazole have been synthesized. Several iridium complexes {iridium(III)bis[2-(3- methoxyphenyl)-1,3-benzothiozolato-N,C2′] acetylacetonate (MeO-BT)2Ir(acac), iridium(III)bis[2-(2,4-difluorophenyl)-1,3- benzothiozolato-N,C2′] acetylacetonate (2F-BT) 2Ir(acac), and iridium(III)bis[2-(2,4-difluorophenyl)-6-fluoro-1,3- benzothiozolato-N,C2′] acetylacetonate (3F-BT) 2Ir(acac)} having different substituents on 2-phenylbenzothiazole have been synthesized. The phosphorescent light emitting diodes (PHOLEDs) using these iridium complexes as dopant emitters were fabricated. The experimental results revealed that the emissive colors of PHOLEDs could be finely tuned by suitable modification of the substituents on the 2-phenylbenzothiazole ligands. Furthermore, these iridium complexes show better emissive properties than the known iridium(III)bis(2-phenylbenzothiozolato-N,C2′) acetylacetonate (BT)2Ir(acac).
- Chang, Wei-Chieh,Hu, Andrew Teh,Duan, Jiun-Pey,Rayabarapu, Dinesh Kumar,Cheng, Chien-Hong
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p. 4882 - 4888
(2007/10/03)
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- Pharmacological profile of 6,12-dihydro-3-methoxy-1-benzopyrano[3,4-b] [1,4]benzothiazin-6-one, a novel human estrogen receptor agonist
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Pharmacological studies were carried out to characterize further the endocrinological profile and the binding mode to the estrogen receptor (ER) of 6,12-dihydro-3-methoxy-l-benzopyrano[3,4-b][1,4]benzothiazin-6-one (1). Binding experiments were conducted with highly purified recombinant human estrogen receptors hERα and β. Potent estrogenic activity of compound 1 was assessed by testing its ability to down-regulate ERs and to enhance estrogen receptor element (ERE)-dependent transcription. The latest step of our work dealt with the synthesis of the 9-fluorinated derivative 15 for ionic microscopy experiments to determine the intracellular localization of compound 1. Although 1 failed to compete with [3H]E2 for binding to both ER isoforms, evidence was reported that it interacted with hERα in MCF-7 cells (ER down-regulation/ERE-dependent luciferase induction). Hence, an appropriate conformation of the hormone binding domain, most probably conferred by co-regulators of ER, is required for the onset of an activity of the compound 1. Estrogenic activity was weak but on the order of magnitude of that of coumestrol (slightly weaker). The synthesis of the 9-methoxylated derivative 16 and its pharmacological evaluation led us to propose a binding mode of 1 on hERα. Compound 1 appears to interact with ERα mainly through interactions of its 3-methoxy substituent with the residue His-524 of the hormone binding domain.
- Jacquot, Yves,Cleeren, Anny,Laios, Ioanna,Ma, Yan,Boulahdour, Athem,Bermont, Laurent,Refouvelet, Bernard,Adessi, Gerard,Leclercq, Guy,Xicluna, Alain
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p. 335 - 341
(2007/10/03)
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- 2-(Anilinomethyl)imidazolines as α1 adrenergic receptor agonists: The discovery of α10 subtype selective 2′-alkylsulfonyl-substituted analogues
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A series of 2′-alkylthio-2-(anilinomethyl)imidazolines were prepared to examine the effect of the alkyl group size, sulfur oxidation state, and phenyl ring substitution on ligand binding and agonism of α-adrenergic receptor subtypes α1a, α1b, α1d, α2a, and α2c. Binding at all receptor subtypes decreased for compounds in the sulfone oxidation state as compared to their sulfide analogues. While sulfides were generally potent, nonselective agonists, sulfones exhibited α1a subtype selectivity in a cell-based functional assay. Sulfone (32) was 250-7000-fold selective for α1a vs all other subtypes.
- Hodson, Stephen J.,Bishop, Michael J.,Speake, Jason D.,Navas III, Frank,Garrison, Deanna T.,Bigham, Eric C.,Saussy Jr., David L.,Liacos, James A.,Irving, Paul E.,Jeffrey Gobel,Sherman, Bryan W.
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p. 2229 - 2239
(2007/10/03)
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- Synthesis and antifungal activity of novel thiazole-containing triazole antifungals. II. Optically active ER-30346 and its derivatives
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A series of novel thiazole-containing triazole antifungals was synthesized and evaluated for antifungal activity against a variety of clinically isolated pathogenic fungi in vitro and against systemic candidosis in vivo. These compounds showed potent antifungal activities in vitro and in vivo. In particular, (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4- difluorophenyl)-1-(1H-1,2,4-triazol-l-yl)-2-butanol (12g; ER-30346) showed potent and well-balanced in vitro activities and potent in vivo efficacy, and had a good safety profile.
- Tsuruoka, Akihiko,Kaku, Yumiko,Kakinuma, Hiroyuki,Tsukada, Itaru,Yanagisawa, Manabu,Nara, Kazumasa,Naito, Toshihiko
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p. 623 - 630
(2007/10/03)
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- Highly selective aldose reductase inhibitors. II. Optimization of the aryl part of 3-(arylmethyl)-2,4,5-trioxoimidazolidine-1-acetic acids
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Accumulation of intracellular sorbitol, the product of glucose reduction catalyzed by aldose reductase (AR) [EC 1.1.1.21], is thought to be the main culprit in the development of diabetic complications. A series of 3- arylalkyl-2,4,5-trioxoimidazolidine-1-acetic acids was prepared and tested for inhibitory activities towards AR and aldehyde reductase (ALR) [EC 1.1.1.2]. These derivatives showed strong inhibitory activity against AR without markedly inhibiting ALR. In particular, the compounds with 3- nitrophenyl, 4-chloro-3-nitrophenyl, and chloro-substituted benzothiazolyl groups as the aryl part showed powerful AR-inhibitory activity. The chloro- substituted benzothiazolyl compound showed an AR selectivity of more than 5000 fold.
- Kotani, Takayuki,Ishii, Akira,Nagaki, Yasuhiro,Toyomaki, Yoshio,Yago, Hisashi,Suehiro, Seishi,Okukado, Nobuhisa,Okamoto, Kaoru
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p. 297 - 304
(2007/10/03)
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- PYRIMIDO-BENZOTHIAZINES
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This invention relates to novel pyrimido-benzothiazine derivative compounds. The compounds of the present invention inhibit the action of the lipoxygenase enzyme and are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals. this invention also relates to pharmaceutical compositions comprising such compounds.
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- Synthesis of Halogen-Substituted 1,5-Benzothiazepine Derivatives and Their Vasodilating and Hypotensive Activities
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In an attempt to improve the effectiveness and duration of the action of diltiazem (1), a 1,5-benzothiazepine calcium channel blocker, its derivatives (2) with halogen substituents on the fused benzene ring were synthesized.These compounds were evaluated for their effects on vertebral and coronary blood flows and antihypertensive activity.The structure-activity relationships are discussed.The 8-chloro derivative ((+)-2b), the most potent compound in this series, was selected for clinical evaluation as a cerebral vasodilating and antihypertensive agent.
- Inoue, Hirozumi,Konda, Mikihiko,Hashiyama, Tomiki,Otsuka, Hisao,Takahashi, Kaoru,et al.
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p. 675 - 687
(2007/10/02)
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- Syntheses of 1,5-Benzothiazepines: Part III - Syntheses of 4-(p-Chlorophenyl)-2-(p-methoxyphenyl)-8-substituted-2,3-dihydro-1,5-benzothiazepines
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4-Methoxy-4'-chlorobenzalacetophenone (IV) on reaction with 5-substituted 2-aminothiophenols (IIIa-f) in toluene gives 4-(p-chlorophenyl)-2-(p-methoxyphenyl)-8-substituted-2,3-dihydro-1,5-benzothiazepines (Va-f).Their structures have been established by IR, PMR and mass spectral data.
- Pant, Umesh C.,Gaur, B. S.,Chugh, Manju
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p. 189 - 190
(2007/10/02)
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