1,4,2-Benzo/pyridodithiazine 1,1-dioxides structurally related to the ATP-sensitive potassium channel openers 1,2,4-Benzo/pyridothiadiazine 1,1-dioxides exert a myorelaxant activity linked to a distinct mechanism of action.

doi:10.1021/jm301743b

Paper

1,4,2-Benzo/pyridodithiazine 1,1-dioxides structurally related to the ATP-sensitive potassium channel openers 1,2,4-Benzo/pyridothiadiazine 1,1-dioxides exert a myorelaxant activity linked to a distinct mechanism of action.

Published Apr 4, 2013 · B. Pirotte, P. de Tullio, Xavier Florence

Journal of medicinal chemistry

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Abstract

The synthesis of diversely substituted 3-alkyl/aralkyl/arylamino-1,4,2-benzodithiazine 1,1-dioxides and 3-alkylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxides is described. Their biological activities on pancreatic β-cells and on smooth muscle cells were compared to those of the reference ATP-sensitive potassium channel (KATP channel) openers diazoxide and 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide. The aim was to assess the impact on biological activities of the replacement of the 1,2,4-thiadiazine ring by an isosteric 1,4,2-dithiazine ring. Most of the dithiazine analogues were found to be inactive on the pancreatic tissue, although some compounds bearing a 1-phenylethylamino side chain at the 3-position exerted a marked myorelaxant activity. Such an effect did not appear to be related to the opening of KATP channels but rather reflected a mechanism of action similar to that of calcium channel blockers. Tightly related 3-(1-phenylethyl)sulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxides were also found to exert a pronounced myorelaxant activity, resulting from both a KATP channel activation and a calcium channel blocker mechanism. The present work highlights the critical importance of an intracyclic NH group at the 4-position, as well as an exocyclic NH group linked to the 3-position of the benzo- and pyridothiadiazine dioxides, for activity on KATP channels.

In Vitro Study

Study Snapshot

Substituted 1,4,2-benzo/pyridodithiazine 1,1-dioxides show myorelaxant activity, with a distinct mechanism of action similar to calcium channel blockers, highlighting the importance of an intracyclic NH group at the 4-position.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

1,4,2-Benzo/pyridodithiazine 1,1-dioxides structurally related to the ATP-sensitive potassium channel openers 1,2,4-Benzo/pyridothiadiazine 1,1-dioxides exert a myorelaxant activity linked to a distinct mechanism of action.

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References

Hydroxylated analogues of ATP-sensitive potassium channel openers belonging to the group of 6- and/or 7-substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides: toward an improvement in sulfonylurea receptor 1 selectivity and metabolism stability.

Hydroxylated analogues of 3-isopropylaminobenzothiadiazine dioxides show improved sulfonylurea receptor 1 selectivity and metabolic stability, making them potential lead candidates for pancreatic tissue treatment.

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The 3-position NH group plays a critical role in optimal activity of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides on insulin-secreting cells and ATP-sensitive potassium channels.

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Citations

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Copper-catalyzed one-pot synthesis efficiently synthesizes 3-N-substituted 1,4,2-benzodithiazine 1,1-dioxide derivatives from 2-halobenzenesulfonamides, amines, and CS2, providing a

Synthesis and vasodilator activity of new 1,4-dihyropyridines bearing sulfonylurea, urea and thiourea moieties

New 1,4-dihydropyridines with urea and thiourea moieties show moderate to strong vasodilator activity, with potential for development of new therapeutics for cardiovascular diseases.

One-Pot, Telescopic Approach for the Chemoselective Synthesis of Substituted Benzo[e]pyrido/pyrazino/pyridazino [1,2-b][1,2,4]thiadiazine dioxides and its Significance in Biological Systems.

This one-pot telescopic approach allows for the chemoselective synthesis of substituted benzo[e]pyrido/pyrazino/pyridazino[1,2-b][1,2,4]thiadiazine dioxides with broad substrate scope and high functional group tolerance,

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This study demonstrates a facile method for regioselective C-H borylation and cross-coupling of 2,1-borazaronaphthalenes, enabling the development of diverse C(8)-substituted 2,1-borazaronaphthalenes.

Method for Accessing Nitrogen-Containing, B-Heteroaryl-Substituted 2,1-Borazaronaphthalenes

This study developed modified reaction conditions to access nitrogen-containing, B-heteroaryl-substituted 2,1-borazaronaphthalenes, enabling a wider range of substructures for various applications.

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This study presents a highly effective method for derivatizing 2,1-borazaronaphthalene cores using ammonium alkylbis(catecholato)silicates via photoredox/nickel dual catalysis, enabling the introduction of various functional groups and inaccessible heterocycl

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Potassium 2-(trifluoroboratomethyl)-2,1-borazaronaphthalenes are efficient nucleophilic building blocks for the synthesis of B-N naphthyl (hetero)arylmethane isosteres, offering a more stable and