- Synthesis, cytotoxic and antioxidant activities of azolyl benzothiazine carboxamides
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Abstract: Azolyl benzothiazine carboxamides were prepared from benzothiazine carboxylate and azolyl amines in the presence of NaOMe under ultrasonication. 4-Bromothiophenylimidazolyl benzothiazine carboxamide (19b) and 4-bromopyrrolylimidazolyl benzothiazine carboxamide (22b) showed cytotoxic activity on HeLa cell lines (IC50 33.75, 47.52?μM) and MCF-7 cell lines (IC5031.75, 34.35?μM). Furthermore, methyl-substituted furanyloxazolyl benzothiazine carboxamide (14a), furanylimidazolyl benzothiazine carboxamide (16a), thiophenyloxazolyl benzothiazine carboxamide (17a) and pyrrolyloxazolyl benzothiazine carboxamide (20a) exhibited antioxidant activity greater than ascorbic acid. Graphical abstract: Azolyl benzothiazine carboxamides are prepared from benzothiazine carboxylate and azolyl amines. Optimization of reaction conditions is established using different molar concentrations of NaOMe. Compounds 19b and 22b showed cytotoxic activity on HeLa cell lines and MCF-7 cell lines. Compounds 14a, 16a, 17a and 20a exhibited prominent antioxidant activity.[Figure not available: see fulltext.].
- Panga, Siva Sankar,Tamatam, Rekha,Adivireddy, Padmaja,Venkatapuram, Padmavathi,Narra, Siva Krishna,Paturu, Kondaiah
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p. 3053 - 3075
(2019/03/13)
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- Synthetic method of piroxicam
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The invention belongs to the field of chemical synthesis, and more specifically relates to a synthetic method of piroxicam. The synthetic method of piroxicam comprises following steps: 1, sodium saccharin and ethyl chloroacetate are taken as initial raw materials, and condensation reaction is carried out so as to obtain 3-oxo-1,2-benzoisothiazoline-2-methyl acetate-1,1-dioxide; 2, sodium methylateis added into the product in step 1, reaction is carried out under catalytic effect of potassium iodide, and 2-methyl-3,4- dioxo-4-oxo-2H-1,-2- benzothiazine-3-carboxylic acid methyl ester-1, 1-dioxide is obtained under the effect of DMSO; 3, the above product is reacted with 2-aminopyridine at 130 DEG C for 10h so as to obtain a high purity finished product. According to the synthetic method, potassium iodide is taken as a catalyst to increase the reaction conversion rate of step 2 obviously, impurity content is controlled effectively; and the total yield is increased to 69%.
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Paragraph 0021; 0025; 0029
(2018/10/27)
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- Synthesis, monoamine oxidase inhibition activity and molecular docking studies of novel 4-hydroxy-N′-[benzylidene or 1-phenylethylidene]-2-H/methyl/benzyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides
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Three series of 4-hydroxy-N′-[benzylidene/1-phenylethylidene]-2-H/methyl/benzyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides (9–11)a-l were synthesized and unraveled to be highly potent dual inhibitors of monoamine oxidases (MAO-A and MAO-B). All the examined compounds demonstrated IC50 values in lower micro-molar range for both MAO-A as well as MAO-B. The most active MAO-A inhibitor was 4-hydroxy-N′-(1-phenylethylidene)-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxide (9i) with an IC50 value of 0.11 ± 0.005 μM, whereas, methyl 4-hydroxy-2H-benzo[e][1,2]thiazine-3-carboxylate 1,1-dioxide (3) was the most active MAO-B inhibitor with an IC50 value of 0.21 ± 0.01 μM. Enzyme kinetics studies revealed that the most potent compounds inhibited both MAO enzymes (A & B) in a competitive fashion. Molecular docking studies were also performed to obtain an intuitive picture of inhibition potential for potent inhibitors. The high potency of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability.
- Saddique, Furqan Ahmad,Zaib, Sumera,Jalil, Saquib,Aslam, Sana,Ahmad, Matloob,Sultan, Sadia,Naz, Humera,Iqbal, Mazhar,Iqbal, Jamshed
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p. 1373 - 1386
(2017/11/13)
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- Hybrid compounds from chalcone and 1,2-benzothiazine pharmacophores as selective inhibitors of alkaline phosphatase isozymes
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Chalcones and 1,2-benzothiazines are two important classes of bioactive compounds, each scaffold endowed with diverse pharmacological activities. Combining both of these pharmacophores in a single molecule was aimed to yield multi-modal agents. Herein, we report a series of hybrid compounds 3a–3o derived from chalcones and 1,2-benzothiazine cores. They were synthesized from commercially available sodium saccharin, and the resulting 1,2-benzothiazine-derived ketone was then condensed with aromatic aldehydes in an aldol condensation to obtain the respective chalcones. The compounds were characterized using different analytical techniques including FT-IR, NMR spectroscopy, mass spectrometry and X-ray crystallography. Some synthesized chalcones revealed potent and/or selective inhibitory properties towards alkaline phosphatase isozymes transiently expressed in COS-7 cells. A detailed structure-activity and selectivity study was carried out with regard to the effect of different substituents at ortho-, meta- and para-positions of the phenyl residue. Compound 3c was the most effective human intestinal alkaline phosphatase (h-IAP) inhibitor (IC50 value of 1.04 μM), while it was not active against human tissue non-specific alkaline phosphatase (h-TNAP) isozyme. In contrast, 3i was a selective inhibitor of h-TNAP with IC50 values of 0.25 ± 0.01 μM. The possible binding interactions of the most effective inhibitors of h-TNAP and h-IAP were obtained from molecular docking studies.
- Ashraf, Adnan,Ejaz, Syeda Abida,Rahman, Shafiq Ur,Siddiqui, Waseeq Ahmad,Arshad, Muhammad Nadeem,Lecka, Joanna,Sévigny, Jean,Zayed, Mohie E. Moustafa,Asiri, Abdullah M.,Iqbal, Jamshed,Hartinger, Christian G.,Hanif, Muhammad
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p. 282 - 291
(2018/10/15)
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- Stereopure Functionalized Benzosultams via Ruthenium(II)-Catalyzed Dynamic Kinetic Resolution-Asymmetric Transfer Hydrogenation
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A highly diastereo- and enantioselective Ru(II)-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenation (DKR-ATH) of α-(N-sulfonylimino) and α-(N-sulfonylamino) aryl ketones to 4-hydroxy-benzo-δ- and 3-(α-hydroxy-arylmethyl)-benzo-γ-sultams is presented. By employing enantiopure ansa-Ru[PipSO2DPEN(CH2)4Ph] cat. II with S/C = 10 000 in a HCO2H/Et3N binary mix, up to >99.9% ee and dr >99:1 are obtained with 100% conversion under mild conditions. Application to access the stereopure "structurally simplified TsDPEN" N,N-ligand syn-3-(α-aminobenzyl)-benzo-γ-sultam ("syn-ULTAM") and its structural isomer trans-4-amino-3-phenyl-benzo-δ-sultam (trans-4) is demonstrated.
- Jeran, Marko,Cotman, Andrej Emanuel,Stephan, Michel,Mohar, Barbara
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supporting information
p. 2042 - 2045
(2017/04/28)
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- Discovery of (2-benzoylethen-1-ol)-containing 1,2-benzothiazine derivatives as novel 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibiting-based herbicide lead compounds
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A series of (2-benzoylethen-1-ol)-containing benzothiazine derivatives was synthesized, and their herbicidal activities were first evaluated. The bioassay results indicated that some of 3-benzoyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide derivatives displayed good herbicidal activity in greenhouse testing, especially, compound 4w had good pre-emergent herbicidal activities against Brassica campestris, Amaranthus retroflexus and Echinochloa crusgalli even at a dosage of 187.5 g ha-1. More importantly, compound 4w displayed significant inhibitory activity against Arabidopsis thaliana HPPD and was identified as the most potent candidate with IC50 value of 0.48 μM, which is better than the commercial herbicide sulctrione (IC50 = 0.53 μM) and comparable with the commercial herbicide mesotrione (IC50 = 0.25 μM). The structure-activity relationships was studied and provided some useful information for improving herbicidal activity. The present work indicated that (2-benzoylethen-1-ol)-containing 1,2-benzothiazine motif could be a potential lead structure for further development of novel HPPD inhibiting-based herbicides.
- Lei, Kang,Hua, Xue-Wen,Tao, Yuan-Yuan,Liu, Yang,Liu, Na,Ma, Yi,Li, Yong-Hong,Xu, Xiao-Hua,Kong, Chui-Hua
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supporting information
p. 92 - 103
(2015/12/31)
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- 4-hydroxy-3-benzoyl-2-alkyl -1,2-benzothiazine -1,1-dioxide derivatives of the (by machine translation)
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The invention relates to a 4-hydroxy-3-benzoyl-2-alkyl -1,2-benzothiazine -1,1-dioxide derivatives, structural formula as (I). wherein: R 1 representative: C1-C5 alkyl; R 2 representative: 2-NO 2, 3-NO 2, 4-NO 2, 2-Br-4-Br, 2-Cl-3-Cl, 2-Cl-5-Cl, 2-Cl-4-F, 2-Cl-4-Br, 2-F-4-Cl, 2-Br-4-F, 2-Br-4-Cl, 2-Cl-4-NO 2, 2-Cl-4-CF 3, 4-SO 2 Me. To saccharines sodium salt as raw materials, by nucleophilic reaction, rearrangement Gabriel-Colman, decarboxylative, alkylation, condensation and Fries rearrangement reaction, the obtained 4-hydroxy-3-benzoyl-2-alkyl -1,2-benzothiazine -1,1-dioxide compound, and the herbicidal activity of the compound to the test, the results show that the compound has a good herbicidal activity, is a novel structure, application prospect of herbicides. (by machine translation)
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Paragraph 0012; 0013
(2016/10/07)
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- 1,2-Benzothiazine 1,1-dioxide carboxylate derivatives as novel potent inhibitors of aldose reductase
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Due to the importance of aldose reductase (ALR2) as a potential drug target in the treatment of diabetic complications, there are increasing interests in design and synthesis of ALR2 inhibitors. Here, we prepared 1,2-benzothiazine 1,1-dioxide acetic acid derivatives and investigated their inhibition activity. Most of these derivatives were found to be active with IC50 values ranging from 0.11 μM to 10.42 μM, and compound 8d, 2-[2-(4-bromo-2- fluorobenzyl)-1,1-dioxido-2H-1,2-benzothiazin-4(3H)-ylidene]acetic acid, showed the most potent inhibition activity. Further, SAR and docking studies suggest that in comparison with the α,β-unsaturated derivatives, the saturated carboxylic acid derivatives had a greater binding affinity with the enzyme and thus an enhanced inhibition activity. Therefore, development of more powerful ARIs based on benzothiazine 1,1-dioxide by stereo-controlled synthesis could be expected.
- Chen, Xin,Zhang, Shuzhen,Yang, Yanchun,Hussain, Saghir,He, Minlan,Gui, Dequan,Ma, Bing,Jing, Chaojun,Qiao, Zhixin,Zhu, Changjin,Yu, Qun
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experimental part
p. 7262 - 7269
(2012/01/03)
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- Microwave assisted synthesis and structure-activity relationship of 4-hydroxy-N′-[1-phenylethylidene]-2H/2-methyl-1,2-benzothiazine-3- carbohydrazide 1,1-dioxides as anti-microbial agents
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A series of 4-hydroxy-N′-[1-phenylethylidene]-2H/2-methyl, 1,2-benzothiazine-3-carbohydrazide 1,1-dioxides was synthesized from commercially available sodium saccharin. Base catalyzed ring expansion of methyl (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)acetate followed by ultrasound mediated hydrazinolysis and subsequent reaction with 1-phenylethanones under the influence of microwaves yielded the title compounds. Besides, microwave assisted synthesis of 1,4-dihydropyrazolo[4,3-c][1,2]benzothiazin-3-ol 5,5-dioxide and 4-methyl-1,4-dihydropyrazolo[4,3-c][1,2]benzothiazin-3-ol 5,5-dioxide is also discussed. Most of the synthesized compounds were found to possess moderate to significant anti-microbial (anti-bacterial and anti-fungal) activities. It is found that compounds with greater lipophilicity (N-methyl analogues) possessed higher anti-bacterial activities.
- Ahmad, Naveed,Zia-Ur-Rehman, Muhammad,Siddiqui, Hamid Latif,Ullah, Muhammad Fasih,Parvez, Masood
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experimental part
p. 2368 - 2377
(2011/06/21)
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- Antioxidant potential of new methyl-4-hydroxy-2h-1,2-benzothiazine-3- carboxylate-1,1-dioxide derivatives
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An easy synthesis of a series of N-alkyl-1,2-benzothiazine-1,1-dioxide derivatives from commercially available saccharine is reported in order to explore their antioxidant potential. The newly synthesized compounds were characterized by spectroscopic techniques (FT-IR, NMR, MS) and single crystal X-ray diffraction analyses. All the synthesized compounds were screened for their DPPH and FRAP analyses to determine their antioxidant activity.
- Arshad, Muhammad Nadeem,Khan, Islam Ullah,Zia-Ur-Rehman, Muhammad,Shafiq, Muhammad
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experimental part
p. 2801 - 2805
(2012/02/02)
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- A facile synthesis of novel biologically active 4-hydroxy-N′-(benzylidene)-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxides
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A novel series of potentially biologically active 4-hydroxy-N′-(benzylidene)-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxides were synthesized starting from ultrasonic mediated N-alkylation of sodium saccharin with methyl chloroacetate. Ring expansion of methyl(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)acetate followed by its hydrazinolysis afforded 4-hydroxy-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide which was reacted in a straight forward manner with various benzaldehydes in an ultrasonic bath to get the title compounds. All of the synthesized compounds were subjected to preliminary evaluation for their antibacterial and DPPH radical scavenging activities.
- Zia-ur-Rehman, Muhammad,Choudary, Jamil Anwar,Elsegood, Mark Robert James,Siddiqui, Hamid Latif,Khan, Khalid Mohammad
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experimental part
p. 1311 - 1316
(2009/09/27)
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- Synthesis of deuterium-labelled meloxicam and piroxicam
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Four step syntheses of deuterium-labelled meloxicam and piroxicam from saccharin via selective CD3I alkylation are described. Labelled oxicams are of great interest for qualitative and/or quantitative isotope dilution-mass spectrometry, coupled with liquid chromatography, currently performed in anti-doping and forensic laboratories. Copyright
- Balssa, Frederic,Bonnaire, Yves
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p. 207 - 210
(2008/01/03)
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- Process for the preparation of crystalline form-1 of 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide
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The present invention is related to an improved process for preparing crystalline Form I of meloxicam, which produces the Form I in high yield.
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Page/Page column 1; 3
(2010/02/15)
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- Synthesis and properties of N-substituted saccharin derivatives
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Four different routes for the synthesis of saccharin containing peptids were studied. While reactions between saccharin sodium and α-halogeno acids were limited to two examples, reactions of sulfobenzoic anhydride (4) or saccharin-N-carboxylate (6) with amino acid esters yielded the ring opened products 5 and 7. Finally, we found, that the reaction between the benzoxathiol derivative 8 and amino acid derivatives represents a versatile route to the peptidic compounds 9 and 11. Hydrolysis and hydrogenolysis were studied, and by combination of the different routes the "saccharin tripeptides" 18 were obtained. Structures and stereochemistry were elucidated by spectroscopic and chromatographic methods. Selected compounds were tested as sweeteners of as inhibitors of elastase, but no exiting results were found.
- Soubh,Besch,Otto, Hans-Hartwig
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p. 384 - 392
(2007/10/03)
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- New quaternary ammonium oxicam derivatives targeted toward cartilage: Synthesis, pharmacokinetic studies, and antiinflammatory potency
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Analogues of nonsteroidal antiinflammatory drugs (NSAIDs) oxicams, in which the active group was linked to a quaternary ammonium function [(4- hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide-3-carboxamido)2- methylpyridinium iodide or piroxicam-N+ and [3-(4-hydroxy-2-methyl-2H-1,2- benzothiazine-1,1-dioxide-3-carboxamido)propyl]trimethylammonium iodide or propoxicam-N+] were synthesized. Compounds were labeled with tritium for piroxicam-N+ and carbon-14 for propoxicam-N+. Pharmacokinetic studies conducted on rats showed that these molecules were able to highly concentrate in joint cartilages but their bioavailability by the oral way was low. Only propoxicam-N+ exhibited a sufficient water solubility to be administered intravenously. This molecule was able to restore proteoglycans biosynthesis in cultured articular chondrocytes treated with Interleukin-1β with an efficiency identical to that of indomethacin. These results suggest that the functionalization of oxicam derivatives by a quaternary ammonium group greatly increases their affinity toward articular cartilage without eliminating their pharmacological activity. New drugs synthesized according to this scheme could be useful to obtain a significant decrease of the efficient administered dose and consequently an attenuation of adverse effects such as digestive toxicity.
- Nicolas, Colette,Verny, Michel,Giraud, Isabelle,Ollier, Monique,Rapp, Maryse,Maurizis, Jean-Claude,Madelmont, Jean-Claude
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p. 5235 - 5240
(2007/10/03)
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- Endothelin receptor antagonists: Synthesis and structure-activity relationships of substituted benzothiazine-1,1-dioxides
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The development of benzothiazine-1,1-dioxide derivatives as a new structural class of potent endothelin receptor antagonists is described. Structure-activity relationships (SAR) revealed that PD164800 (1) is a potent antagonist of the ET(A) receptor subtype. Copyright (C) 1998 Elsevier Science Ltd.
- Berryman,Edmunds,Bunker,Haleen,Bryant,Welch,Doherty
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p. 1447 - 1456
(2007/10/03)
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- Effect of structural modification of enol-carboxamide-type nonsteroidal antiinflammatory drugs on COX-2/COX-1 selectivity
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Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. In subsequent screening in microsomal assays using human COX-1 and COX-2, we discovered that it possessed a selectivity profile for COX-2 superior to piroxicam and other marketed NSAIDs. We therefore embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by structural modification. Substitution at the 6- and 7-positions of the 4-oxo-1,2-benzothiazine-3- carboxamide, alteration of the N-methyl substituent, and amide modification were all examined. In addition we explored several related systems including the isomeric 3-oxo-1,2-benzothiazine-4-carboxamides, thienothiazines, indolothiazines, benzothienothiazines, naphthothiazines, and 1,3- and 1,4- dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no compound tested had a better COX-2/COX-1 selectivity profile than that of 5.
- Lazer, Edward S.,Miao, Clara K.,Cywin, Charles L.,Sorcek, Ronald,Wong, Hin-Chor,Meng, Zhaoxing,Potocki, Ian,Hoermann, MaryAnn,Snow, Roger J.,Tschantz, Matt A.,Kelly, Terence A.,McNeil, Daniel W.,Coutts, Simon J.,Churchill, Laurie,Graham, Anne G.,David, Eva,Grob, Peter M.,Engel, Wolfhard,Meier, Hans,Trummlitz, Günter
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p. 980 - 989
(2007/10/03)
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- A facile one-pot synthesis of 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-1,2-benzothiazine 1,1-dioxide, a key intermediate in the synthesis of oxicam anti-inflammatory agents
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4-Hydroxy-3-methoxycarbonyl-2-methyl-2H-1,2-benzothiazine 1,1-dioxide (8) was synthesized by a one-pot procedure, starting from the readily available saccharine. The synthesis involves 4 transformations with an overall yield equivalent to that from the stepwise process.
- Manjarrez, Norberto,Perez, Herminia I.,Solis, Aida,Luna, Hector
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p. 585 - 591
(2007/10/03)
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- A facile one-pot synthesis of 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-1,2-benzothiazine 1,1-dioxide, a key intermediate in the synthesis of oxicam anti-inflammatory agents
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4-Hydroxy-3-methoxycarbonyl-2-methyl-2H-1,2-benzothiazine 1,1-dioxide (8) was synthesized by a one-pot procedure, starting from the readily available saccharine. The synthesis involves 4 transformations with an overall yield equivalent to that from the stepwise process.
- Manjarrez,Perez,Solis,Luna
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p. 1405 - 1410
(2007/10/03)
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- Synthesis of -yl>ketene S,S-Acetals and Their Reaction with Hydrazine Hydrate
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The previously unknown ketene S,S-acetals 2, 3, and 4 are prepared by dithiocarboxylation reaction of methylene-active saccharin derivatives 1 in the presence of sodium hydride/carbon disulfide in dry DMF followed by alkylation.Compounds 2a, 3a, and 4a are treated with hydrazine hydrates (85percent) to give 2-hydrazono-3,3-bis(methylthio)propiophenone (6a) and methyl or ethyl pyruvate 6b or 6c, respectively.
- Doelling, Wolfgang,Herrmann, Cornelia,Augustin, Manfred
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p. 927 - 929
(2007/10/02)
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- PHASE TRANSFER CATALYSED N-SUBSTITUTION OF 2H-1,2-BENZISOTHIAZOLIN-3-ONE 1,1-DIOXIDE
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The title compound on reaction with alkylating reagents and under the conditions of phase catalysis affords 2-substituted 2H-1,2-benzisothiazolin-3-one 1,1-dioxides (III).The conditions of the reaction and the mass spectra of the products are discussed.
- Svoboda, Jiri,Palecek, Jaroslav,Dedek, Vaclav
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p. 1304 - 1310
(2007/10/02)
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- 3-Oxo-1,2-benzoisothiazoline-2-acetic Acid 1,1-Dioxide Derivatives. I. Reaction of Esters with Alkoxides
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Reaction of 3-oxo-1,2-benzoisothiazoline-2-acetic acid alkyl esters 1,1-dioxide (1a-d) with alkaline alkoxides was carried out under various conditions.Under mild conditions, o-(N-carboxymethylsulfamyl)benzoic acids dialkyl esters (2a-d) were obtained with good yields.Reaction of 1a-d or 2a-d with sodium alkoxide under drastic conditions afforded 4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid alkyl esters 1,1-dioxide (3a-d).Transesterification was observed when esters 1b-d were treated with sodium methoxide in methanol.Esters 3a-d were hydrolyzed in concentrated aqueous sodium hydroxide affording the acid 6.Attempts to recrystallize 6 from water resulted in its decarboxylation to give 2H-1,2-benzothiazine-4-(3H)one 1,1-dioxide (7).Compound 6 could not be obtained by acid hydrolysis of esters 3a-d or by rearrangement of 3-oxo-1,2-benzoisothiazoline-2-acetic acid 1,1-dioxide (8).Different experimental evidence supports the suggestion that rearrangement took place by ethanolysis of the carboxamide linkage affording the open sulfonamides (fast step) followed by a Dieckmann cyclization (slow step).It was demonstrated that transesterification took place in the open sulfonamides 2.
- Schapira, Celia B.,Perillo, Isabel A.,Lamdan, Samuel
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p. 1281 - 1288
(2007/10/02)
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