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Yuriy G. Shermolovich - One of the best experts on this subject based on the ideXlab platform.
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1 oxo 1 fluoro 1 2 4 Benzothiadiazines a new type of cyclic sulfonimidoyl fluorides
Journal of Fluorine Chemistry, 2014Co-Authors: Natalia P. Kolesnik, Alexander B. Rozhenko, Vasyl Kinzhybalo, Tadeusz Lis, Yuriy G. ShermolovichAbstract:Abstract An approach to the synthesis of the novel cyclic sulfonimidoyl fluorides was elaborated based on the electrophilic fluorination of 1-oxo-2H-1,2,4-benzothiadizines with Selectfluor®. Crystal structure of 1-oxo-1-fluoro-3-phenyl-1,2,4-benzothiadiazine was determined.
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1-Oxo-1-fluoro-1,2,4-Benzothiadiazines—A new type of cyclic sulfonimidoyl fluorides
Journal of Fluorine Chemistry, 2014Co-Authors: Natalia P. Kolesnik, Alexander B. Rozhenko, Vasyl Kinzhybalo, Tadeusz Lis, Yuriy G. ShermolovichAbstract:Abstract An approach to the synthesis of the novel cyclic sulfonimidoyl fluorides was elaborated based on the electrophilic fluorination of 1-oxo-2H-1,2,4-benzothiadizines with Selectfluor®. Crystal structure of 1-oxo-1-fluoro-3-phenyl-1,2,4-benzothiadiazine was determined.
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The synthesis of chiral 1,2,4-benzothiadiazine derivatives
Tetrahedron: Asymmetry, 2007Co-Authors: Nadiia V. Briukhovetska, Nataliya P. Kolesnyk, Alexander M. Chernega, Sergiy A. Buth, Yuriy G. ShermolovichAbstract:Abstract Novel enantiomerically pure Benzothiadiazines were prepared using the commercially available enantiopure (1R,2S,5R)-(−)-menthol and 1,7-dichloro-3-trifluoromethyl-1λ4-benzo[1,2,4]thiadiazine.
Pascal De Tullio - One of the best experts on this subject based on the ideXlab platform.
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7-Phenoxy-Substituted 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency
Journal of Medicinal Chemistry, 2017Co-Authors: Eric Goffin, Pascal De Tullio, Thomas Drapier, Anja Probst Larsen, Pierre Geubelle, Christopher P. Ptak, Saara Laulumaa, Karoline Rovinskaja, Julie Gilissen, Lars OlsenAbstract:We report here the synthesis of 7-phenoxy-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of substitution on the phenoxy ring and on the nitrogen atom at the 4-position was examined. At GluA2(Q) expressed in HEK293 cells (calcium flux experiment), the most potent compound was 11m (4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, EC50 = 2.0 nM). The Hill coefficient in the screening and the shape of the dimerization curve in small-angle X-ray scattering (SAXS) experiments using isolated GluA2 ligand-binding domain (GluA2-LBD) are consistent with binding of one molecule of 11m per dimer interface, contrary to most benzothiadiazine dioxides developed to date. This observation was confirmed by the X-ray structure of 11m bound to GluA2-LBD and by NMR. This is the first benzothiadiazine dioxide AMPApam to reach the nanomolar range.
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Impact of the nature of the substituent at the 3-position of 4H-1,2,4-benzothiadiazine 1,1-dioxides on their opening activity toward ATP-sensitive potassium channels.
Journal of Medicinal Chemistry, 2011Co-Authors: Bernard Pirotte, Pascal De Tullio, Stéphane Boverie, Catherine Michaux, Philippe LebrunAbstract:The synthesis of diversely substituted 3-isopropoxy-, 3-isopropylsulfanyl-, 3-isopropylsulfinyl-, and 3-isobutyl-4H-1,2,4-benzothiadiazine 1,1-dioxides is described. Their activity on pancreatic β-cells (inhibitory effect on the insulin releasing process) and on vascular and uterine smooth muscle tissues (myorelaxant effects) was compared to that of previously reported K(ATP) channel openers belonging to 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides. The present study aimed at evaluating the impact on biological activity of the isosteric replacement of the NH group of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides by a O, S, S(═O), or CH(2) group. By comparing compounds bearing identical substituents, the following rank order of potency on pancreatic β-cells was observed: 3-isopropylamino > 3-isobutyl > 3-isopropoxy > 3-isopropylsulfanyl > 3-isopropylsulfinyl-substituted 4H-1,2,4-benzothiadiazine 1,1-dioxides (NH > CH(2) > O > S > S(═O)). A molecular modeling study revealed that 3-isopropoxy-, 3-isopropylsulfanyl-, and 3-isopropylamino-substituted compounds adopted a similar low-energy conformation (preferred orientation of the isopropyl chain). Moreover, no direct relationship was detected between the conformational freedom of the different classes of Benzothiadiazines (from the most to the lowest conformationally constrained compounds: NH > O > S > CH(2)) and their biological activity on insulin-secreting cells. Therefore, the present study confirmed the critical role of the NH group at the 3-position for the establishment of a strong hydrogen bond responsible for optimal activity expressed by 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides on insulin-secreting cells. Radioisotopic and fluorimetric experiments conducted with 7-chloro-3-isopropoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide 10c demonstrated that such a compound, bearing a short branched O-alkyl group instead of the NH-alkyl group at the 3-position, also behaved as a specific K(ATP) channel opener. Lastly, the present work further identified 3-(alkyl/aralkyl)sulfanyl-substituted 7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides as a class of promising myorelaxant drugs acting on uterine smooth muscles, at least in part, through the activation of K(ATP) channels.
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New substituted aryl esters and aryl amides of 3,4-dihydro-2H-1,2,4- benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors
MedChemComm, 2011Co-Authors: Gaëlle Dintilhac, Bernard Pirotte, Deniz Arslan, Sébastien Dilly, L. Danober, Iuliana Botez, Pierre Lestage, Pascal De TullioAbstract:AMPA receptor potentiators belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been found to be of great interest as cognitive enhancers. Previous structure–activity relationships have demonstrated the importance for activity of the nature of the substituent at the 7-position of the heterocycle. This work aims to explore the impact on AMPA potentiation of the introduction of different aryl and aralkyl ester or aryl amide groups at the 7-position. The new synthesized compounds were evaluated as AMPA receptor potentiators by examining their effect on rat brain primary cell cultures on AMPA-evoked membrane depolarisation using fluorescent membrane potential dyes and on imaging-based plate reader. The most potent compound of this series was 2-methylphenyl 4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide 16c which provoked a strong potentiation of AMPA current with a potency close to that reported for the best reference compounds of the benzothiadiazine class (i.ecyclothiazide). This work also revealed that only the ortho-substitution of the phenyl group of 1,2,4-benzothiadiazine-7-carboxylate esters provided potent AMPA receptor potentiators opening the way to further chemical exploration.
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Effect on K(ATP) channel activation properties and tissue selectivity of the nature of the substituent in the 7- and the 3-position of 4H-1,2,4-benzothiadiazine 1,1-dioxides.
Journal of Medicinal Chemistry, 2005Co-Authors: Stéphane Boverie, Bernard Pirotte, Philippe Lebrun, Marie-hélène Antoine, Fabian Somers, B. Becker, Sophie Sebille, Raogo Ouedraogo, Stéphane Counerotte, Pascal De TullioAbstract:The present work explored 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides diversely substituted in the 7-position. Those compounds, structurally related to previously described potassium channel openers such as the benzothiadiazine dioxide BPDZ 73, were tested as putative K(ATP) channel activators on the pancreatic endocrine tissue and on the vascular smooth muscle tissue. The nature of the substituent introduced in the 7-position as well as the nature of the alkylamino side chain in the 3-position strongly affected both potency and tissue selectivity of 4H-1,2,4-benzothiadiazine 1,1-dioxides. Thus, compounds bearing in the 7-position a methyl or a methoxy group or devoid of a substituent in this position, and bearing an ethyl, an isopropyl, or a cyclobutylamino group in the 3-position were found to be potent and selective inhibitors of insulin release from rat pancreatic B-cells (i.e. 10a, 10b, 12b, 12d, 22c). In contrast, 3-alkylamino-7-trifluoromethyl- (20a-c) and 3-alkylamino-7-pentyl-4H-1,2,4-benzothiadiazine 1,1-dioxides (11a,b) expressed a marked myorelaxant activity on rat aorta ring. Among the latter compounds, the 3-alkylamino-7-pentyl derivative (11a) showed a clear selectivity for the vascular smooth muscle tissue. The present work gives new insights into the role of the substituent in both the 7- and the 3-position for the design of 4H-1,2,4-benzothiadiazine 1,1-dioxide potassium channel openers exhibiting different tissue selectivity profiles.
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Toward Tissue-Selective Pancreatic B-Cells KATP Channel Openers Belonging to 3-Alkylamino-7-halo-4H-1,2,4-benzothiadiazine 1,1-Dioxides
Journal of Medicinal Chemistry, 2003Co-Authors: Pascal De Tullio, Stéphane Boverie, Marie-hélène Antoine, Fabian Somers, B. Becker, Sophie Sebille, Raogo Ouedraogo, Michael Dabrowski, Philip Wahl, John Bondo HansenAbstract:3-(Alkylamino)-7-halo-4H-1,2,4-benzothiadiazine 1,1-dioxides were synthesized, and their activity on rat-insulin-secreting cells and rat aorta rings was compared to that of the K(ATP) channel activators diazoxide and pinacidil. Structure-activity relationships indicated that an improved potency and selectivity for the pancreatic tissue was obtained by introducing a fluorine atom in the 7-position and a short linear (preferably ethyl) or cyclic (preferably cyclobutyl) hydrocarbon chain on the nitrogen atom in the 3-position. By contrast, strong myorelaxant activity was gained by the introduction of a halogen atom different from the fluorine atom in the 7-position and a bulky branched alkylamino chain in the 3-position. Thus, 3-(ethylamino)-7-fluoro-4H-1,2,4-benzothiadiazine 1,1-dioxide (11) expressed a marked inhibitory activity on pancreatic B-cells (IC(50) = 1 microM) associated with a weak vasorelaxant effect (ED(50) > 300 microM), whereas 7-chloro-3-(1,1-dimethylpropyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide (27), which was only slightly active on insulin-secreting cells (IC(50) > 10 microM), was found to be very potent on vascular smooth muscle cells (ED(50) = 0.29 microM). Radioisotopic and electrophysiological investigations performed with 7-chlorinated, 7-iodinated, and 7-fluorinated 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides confirmed that the drugs activated K(ATP) channels. The present data revealed that subtle structural modifications of 3-(alkylamino)-7-halo-4H-1,2,4-benzothiadiazine 1,1-dioxides can generate original compounds activating K(ATP) channels and exhibiting different in vitro tissue selectivity profiles.
Natalia P. Kolesnik - One of the best experts on this subject based on the ideXlab platform.
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1 oxo 1 fluoro 1 2 4 Benzothiadiazines a new type of cyclic sulfonimidoyl fluorides
Journal of Fluorine Chemistry, 2014Co-Authors: Natalia P. Kolesnik, Alexander B. Rozhenko, Vasyl Kinzhybalo, Tadeusz Lis, Yuriy G. ShermolovichAbstract:Abstract An approach to the synthesis of the novel cyclic sulfonimidoyl fluorides was elaborated based on the electrophilic fluorination of 1-oxo-2H-1,2,4-benzothiadizines with Selectfluor®. Crystal structure of 1-oxo-1-fluoro-3-phenyl-1,2,4-benzothiadiazine was determined.
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1-Oxo-1-fluoro-1,2,4-Benzothiadiazines—A new type of cyclic sulfonimidoyl fluorides
Journal of Fluorine Chemistry, 2014Co-Authors: Natalia P. Kolesnik, Alexander B. Rozhenko, Vasyl Kinzhybalo, Tadeusz Lis, Yuriy G. ShermolovichAbstract:Abstract An approach to the synthesis of the novel cyclic sulfonimidoyl fluorides was elaborated based on the electrophilic fluorination of 1-oxo-2H-1,2,4-benzothiadizines with Selectfluor®. Crystal structure of 1-oxo-1-fluoro-3-phenyl-1,2,4-benzothiadiazine was determined.
Ji-wang Chern - One of the best experts on this subject based on the ideXlab platform.
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Studies on 1,2,4-benzothiadiazine 1,1-dioxides VII1 and quinazolinones IV2: synthesis of novel built-in hydroxyguanidine tricycles as potential anticancer agents
HETEROCYCLES, 1993Co-Authors: Ji-wang Chern, Jiann-gwo Rong, Yen-chywan Liaw, Chien Shu Chen, Chien-lin Huang, Chao-han Chan, Andrew H.-j. WangAbstract:Two representative built-in hydroxyguanidine tricycles containing 1,2,4-benzothiadiazine 1,1-dioxides (3) and quinazolinones (4) were prepared by reductive cyclization of 1-(2-nitrophenylsulfonyl)-2-benzylthio-2-imidazoline (9a), 1-(2-nitrophenylsulfonyl)-2-benzylthio-1,4,5,6-tetrahydropyrimidine (9b), 1-(2-nitrobenzoyl)-2-benzylthio-2-imidazolidine (10a) and 1-(2-nitrobenzoyl)-2-benzylthio-1,4,5,6-tetrahydropyrimidine hydrobromide respectively (10b) with zinc dust in acetic acid under ice-cooling. 2,10-Dihydro-10-hydroxy-3H-imidazo[1,2-b][1,2,4]benzothiadiazine 5,5-dioxide (3a) and 2,3,4,11-tetrahydro-11-hydroxypyrimido[1,2-b][1,2,4]benzothiadiazine 6,6-dioxide (3b) were found to be active against solid tumor cell lines such as KB, Colo 205, HeLa, and Hepa-2
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1,2,4-Benzothiadiazine 1,1-Dioxides, Part 4: Mitsunobu Reactions of 3-Hydroxyalkylamino- and 3-Mercaptoalkylamino-4H1, 2,4-benzothiadiazine 1,1-Dioxides. A Convenient Synthesis of Built-in Guanidine Tricycles and Disulfides
Synthesis, 1991Co-Authors: Ji-wang Chern, Chia-yang ShiauAbstract:3-(2-Hydroxyethyl)amino- and 3-(3-hydroxypropyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxides were treated with triphenylphosphine in the presence of diethyl azodicarboxylate leading to the formation 2,4-dihydro-1H-imidazo[2,1-c][1,2,4]benzothiadine 5,5-dioxide and 1,2,3,5-tetrahydropyrimido[2,1-c][1,2,4]benzothiadiazine 6,6-dioxide, respectively. However, under the same conditions, the oxidized productsd bis[2-(1,1-dioxo-4H-1,2,4-benzothiadazin-3-ylamin)ethyl] disulfide and bis[2-(1,1-dioxo-4H-1,2,4-benzothiadiazin-3-ylamino)propyl] disulfide were obtained from 3-(2-mercaptoethyl)amino- and 3-(3-mercaptopropy)amino-4H-1,2,4-benzothiadiazine 1,1-dioxides.
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1,2,4 Benzothiadiazine 1,1-dioxide. V: 1 synthesis of built-in hydroxuguanidine tricycles as potential anticancer agents
Tetrahedron Letters, 1991Co-Authors: Ji-wang Chern, Jiann-gwo RongAbstract:Two representative built in hydroxyguanidine tricycles, 10-N-hydroxy-2,3-dihydroimidazol [1,2-b][1,2,4]benzothiadiazine 5,5-dioxide (la) and 11-N-hydroxy-2,3-dihydro-4H-pyrimido-[l,2-c] [l,2,4]benzothiadiazine 6,6-dioxide (lb), were obtained in 78% and 30% yields, respectively by a treatment of 1-(2-nitrobenzenesulfonyl)-2-benzylthio-2-imidazolidine and -4,5-dihydro-6H-pyrimidine with zinc in acetic acid under ice-cooling for 30 min.
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SYNTHESIS OF 3-(MERCAPTOALKYL)- AND 3-(HYDROXYALKYL)-AMINO-2H-1,2,4-BENZOTHIADIAZINE 1,1 DIOXIDES
Phosphorus Sulfur and Silicon and the Related Elements, 1991Co-Authors: Ji-wang Chern, Kang-chien LiuAbstract:Abstract The synthesis and Mitsunobu reaction of 3-(mercapto-alkyl)- and 3-(hydroxyalkyl)-amino-2H-1,2,4-benzothiadiazine 1,1-dioxides (10a,b) from 2-(chloroalkylthioureido)- and 2-(chloroalkylureido)-benzenesulfonamide (5) are discussed.
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1,2,4‐benzothiadiazine 1,1‐dioxides 3. Reactions of 2‐aminobenzenesulfonamide with chloroalkyl isocyanates
Journal of Heterocyclic Chemistry, 1990Co-Authors: Ji-wang Chern, Jiann-gwo Rong, Kang-chien Liu, Ming-chu Cheng, Yu WangAbstract:Reactions of 2-aminobenzenesulfonamide (1) with allyl, methyl, 2-chloroethyl aor 3-chloropropyl isocyanates gave 2-(methylureido)-, 2-(allylureido)-, 2-(2′-chloroethylureido)- and 2-(3′-chloropropylureido)-benzene sulfonamides 3a,b and 7a,b in excellent yields. Treatment of 3a,b at refluxing temperature of DMF afforded 2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide (4) in good yield. However, when compounds 7a,b were refluxed in 2-propanol, 3-(2′-aminoethoxy)-2H-1,2,4-benzothiadiazine 1,1-dioxide (11a) and 3-(3′-aminopropoxy)-2H-1,2,4-benzothiadiazine 1,1-dioxide (11b) were obtained in a form of the hydrochloride salts 10a,b in 87% and 78% yields respectively. Heating 11b in ethanol gave a dimeric form of 2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide and 3-(3′-aminopropoxy)-2H-1,2,4-benzothiadiazine 1,1-dioxide (12) in 55% yield. Treating of 7a,b or 11a,b with triethylamine at the refluxing temperature of 2-propanol afforded 3-(2′-hydroxyethylamino)-2H-1,2,4-benzothiadiazine 1,1-dioxide (2a) and 3-(3′-hydroxypropylamine)-2H-1,2,4-benzothiadiazine 1,1-dioxide (2b) via a Smiles rearrangement.
Balázs Volk - One of the best experts on this subject based on the ideXlab platform.
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Transformation of 2H-1,2,3-benzothiadiazine 1,1-dioxides variously substituted at the aromatic ring, via nucleophilic substitution and demethylation reactions
Synthetic Communications, 2020Co-Authors: Imre Gyűjtő, Márta Porcs-makkay, Gyula Simig, Ernák Ferenc Várda, Gyöngyvér Pusztai, Gábor Tóth, Balázs VolkAbstract:2H-1,2,3-Benzothiadiazine 1,1-dioxides are a class of compounds of pharmacological interest. After earlier studies carried out at our laboratory on various transformations (alkylation, acylation, a...
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Synthesis and Chemistry of 1,2,3-Benzothiadiazine 1,1-Dioxide Derivatives: A Comprehensive Overview
Chemistry, 2020Co-Authors: Imre Gyűjtő, Márta Porcs-makkay, Gyula Simig, Balázs VolkAbstract:1,2,4-Benzothiadiazine 1,1-dioxide derivatives (e.g., chlorothiazide, hydrochlorothiazide) have been long used in the human therapy as diuretic and antihypertensive agents. Marketed drugs containing the structurally related phthalazinone scaffold are applied for the treatment of various diseases ranging from ovarian cancer to diabetes and allergy. 1,2,3-Benzothiadiazine 1,1-dioxides combine the structural features of these two compound families, which led to their more intensive research since the 1960s. In the present review, we summarize the literature of this period of more than half a century, including all scientific papers and patent applications dealing with the synthesis and reactions of this compound family, briefly hinting at their potential therapeutic application as well.
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Synthesis and base-mediated rearrangement of 3-acetyl-2-methyl-3,4-dihydro-2H-1,2,3-benzothiadiazine 1,1-dioxides
Tetrahedron, 2016Co-Authors: Márta Porcs-makkay, Imre Gyűjtő, Gyula Simig, Balázs VolkAbstract:Abstract In continuation of our studies on the acetylation and alkylation reactions of 3,4-dihydro-2H-1,2,3-benzothiadiazine 1,1-dioxides, a 3-acetyl-2-methyl derivative was synthesized. Attempted reduction of the 3-acetyl moiety to an ethyl group with LiAlH4 led surprisingly to the corresponding 2,3-dihydro-1,2-benzisothiazol 1,1-dioxide, a ring-contracted product. The possible mechanisms of this new, base-mediated rearrangement reaction are discussed. The reaction conditions were optimized by using various bases, and the rearrangement reaction was extended to compounds exhibiting various substituents at the 4-position of the benzothiadiazine ring system.