Biological properties of two enantiomorphic forms ofN-(2,6-dimethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, a structural analogue of piroxicam

Shishkina, Svitlana V.; Украинец, И. В.; Vashchenko, O. V.; Волощук, Н. І.; Bondarenko, P. S.; Petrushova, L. A.; Sim, Galina

doi:10.1107/s2053229619016450

Cited by 3 publications

(2 citation statements)

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“…As we have shown repeatedly before, the spatial structure o of 4-R-2,2-dioxo-1H-2λ 6 ,1benzothiazine-3-carboxylic acids derivatives can significantly affect their biological properties [22][23][24][25][26]. On the other hand, it is well known that salt formation by 4-ОН group is accompanied by drastic changes of 4-hydroxy-2,2-dioxo-1H-2λ 6 ,1-benzothiazines crystal molecular conformations [18,27].…”

Section: The Molecular and Crystal Structure Studymentioning

confidence: 76%

Methyl 4-Hydroxy-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxylate and Its Analogs Modified in the Benzene Moiety of the Molecule as New Analgesics

et al. 2020

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In order to identify new regularities of the “structure–analgesic activity” relationship in the series of 2,1-benzothiazine derivatives, the synthesis of methyl 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate and a group of its analogs substituted in the benzene moiety of the molecule, as well as their mono-and diammonium salts, was performed with tris(hydroxymethyl)aminomethane. The algorithm was proposed; it allows for uniquely solving the question of the nature of the substituent and its true position in the benzothiazine core based on the complex use of NMR (1H and 13C) and mass spectrometry data. Using single-crystal X-ray diffraction analysis it was proven that salt formation first passes through the cyclic sulfamide group and only then through the 4-hydroxyl group, and is always accompanied by a significant conformational rearrangement of the molecule. Based on the results of pharmacological tests it was found that modification of the benzene moiety of the molecule can be used as a method for enhancing the analgesic properties of the class of compounds studied. The presence of a substitute in position 7 is particularly effective, regardless of its nature. A comparative analysis of the analgesic activity of the initial esters and their mono- and diammonium salts convincingly showed that the common belief about a direct relationship between the solubility of a substance and the level of its biological effect is not always true. As it turned out, increasing the solubility in water can lead to a variety of consequences: From a significant increase in analgesia to its complete elimination. It was suggested that the analgesic activity of the compounds studied is determined not by solubility, but by the molecular conformations formed during their obtainment.

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Section: The Molecular and Crystal Structure Studymentioning

confidence: 76%

Methyl 4-Hydroxy-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxylate and Its Analogs Modified in the Benzene Moiety of the Molecule as New Analgesics

et al. 2020

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“…To analyze the possibility of the existence of the similar compounds in different tautomeric forms, a search of the Cambridge Structural Database (CSD Version 5.41, update of June 2022; Groom et al, 2016) for the benzothiazine fragment was performed. Of the 45 hits found, 19 reported the enol form of this fragment [refcodes: AKIJIP, AKIJIP01 (Ukrainets et al, 2016b), CABBEP (Lei et al, 2016), DUCBEL, DUCBEL01 (Shishkina et al, 2020b), IJUJAA (Ukrainets et al, 2015b), LANNUM (Ukrainets et al, 2016a), LOGHEW (Ukrainets et al, 2014a), MINJAW (Shishkina et al, 2013), NODGUK (Ukrainets et al, 2013), NOXJOC (Lei et al, 2019), RACQUL (Shishkina et al, 2020a), TAJXUB, TAJXUB01, TAJXUB02 (Ukrainets et al, 2020a), UWUCIA (Ukrainets et al, 2015a), XEKPUB (Ukrainets et al, 2017), ZUZJIQ, ZUZJOW (Ukrainets et al, 2020b)], while the keto form was detected in 12 hits [refcodes: KANTIE (Shafiq et al, 2011), LIVPUC (Tahir et al, 2008), LIVQAJ (Shafiq et al, 2008a), MOTDOP (Shafiq et al, 2009b), PONWEV (Shafiq et al, 2009d), SEJWAI (Shishkina et al, 2017), SOGDOI (Shafiq et al, 2008b), SOLKOU (Shafiq et al, 2009a), UZAMOZ (Ukrainets et al, 2014b), VACKER (Khan et al, 2010), WACRUP (Shafiq et al, 2010), YOVBER (Shafiq et al, 2009c)]. Both of these two forms are presented in structure NAKZAD (Lega et al, 2016c).…”

Section: Database Surveymentioning

confidence: 99%

3,3′-(Phenylmethylene)bis(1-ethyl-3,4-dihydro-1H-2,1-benzothiazine-2,2,4-trione): single-crystal X-ray diffraction study, quantum-chemical calculations and Hirshfeld surface analysis

et al. 2023

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The title compound, C27H26N2O6S2, possesses potential antimicrobial, analgesic, and anti-inflammatory activity. This compound has three tautomeric forms, which relative energies were estimated with quantum-chemical calculations. All these tautomers (dienol form 7A, keto–enol form 7B, and diketo form 7C) were optimized by the M06–2X/cc-pVTZ method in a vacuum, using the PCM model with chloroform and DMSO as solvent. The diketo form of the title compound proved to be the most energetically favourable as compared to the keto–enol or dienol forms. The diketo form can exist as three possible stereoisomers with the same configuration of one stereogenic center and different configurations of the stereogenic centers at two other atoms: ( R , R , R ), (S , R , S ) and ( R , R , S ). The ( R , R , S ) stereoisomer was found in the crystal phase. It was revealed that the thiazine rings of equivalent benzothiazine fragments have different conformations, (a sofa or a half-chair). The two bicyclic fragments connected through the phenylmethylene group are oriented almost orthogonal to each other, subtending a dihedral angle of 82.16(7)°.

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1-Allyl-4-hydroxy-2,2-dioxo-N-(4-methoxyphenyl)-1H-2λ⁶,1-benzothiazine-3-carboxamide: polymorphic transition due to grinding with the loss of the biological activity

Shishkina

Shaposhnyk

Баумер

et al. 2022

Acta Crystallogr Sect B

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A study of two polymorphic forms of 1-allyl-4-hydroxy-2,2-dioxo-N-(4-methoxyphenyl)-1-2λ6,1-benzothiazine-3-carboxamide (a structural analogue of piroxicam) has revealed some regularities in the crystal structure formation due to different evaporation rates from the tested solvents. The monoclinic polymorph crystallized from ethyl acetate is formed due to a large number of very weak C—H...O and C—H...π interactions as well as one strong stacking interaction. The triclinic polymorph crystallized from N,N-dimethylformamide is formed due to a small number of weak specific interactions and a maximal number of strong stacking interactions. The stacked dimer is a complex building unit in both polymorphic structures. Further analysis showed that the monoclinic structure is layered while the triclinic one is columnar. The two polymorphic structures also differ in their biological activity (antidiuretic and analgesic). The monoclinic polymorph possesses very high biological activity while the triclinic polymorph is almost inactive. The polymorphic transition of the biologically active metastable monoclinic structure into the inactive stable triclinic one within four weeks of grinding is caused by orientational factors rather than conformational ones and is accompanied by a change in the redistribution of interaction energies in the crystal from anisotropic to more isotropic. Thus, a slow polymorphic transition after grinding results in a loss of the biological activity.

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Biological properties of two enantiomorphic forms ofN-(2,6-dimethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxamide, a structural analogue of piroxicam

Cited by 3 publications

References 22 publications

Methyl 4-Hydroxy-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxylate and Its Analogs Modified in the Benzene Moiety of the Molecule as New Analgesics

Methyl 4-Hydroxy-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxylate and Its Analogs Modified in the Benzene Moiety of the Molecule as New Analgesics

3,3′-(Phenylmethylene)bis(1-ethyl-3,4-dihydro-1H-2,1-benzothiazine-2,2,4-trione): single-crystal X-ray diffraction study, quantum-chemical calculations and Hirshfeld surface analysis

1-Allyl-4-hydroxy-2,2-dioxo-N-(4-methoxyphenyl)-1H-2λ⁶,1-benzothiazine-3-carboxamide: polymorphic transition due to grinding with the loss of the biological activity

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Biological properties of two enantiomorphic forms ofN-(2,6-dimethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, a structural analogue of piroxicam

Cited by 3 publications

References 22 publications

Methyl 4-Hydroxy-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxylate and Its Analogs Modified in the Benzene Moiety of the Molecule as New Analgesics

Methyl 4-Hydroxy-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxylate and Its Analogs Modified in the Benzene Moiety of the Molecule as New Analgesics

3,3′-(Phenylmethylene)bis(1-ethyl-3,4-dihydro-1H-2,1-benzothiazine-2,2,4-trione): single-crystal X-ray diffraction study, quantum-chemical calculations and Hirshfeld surface analysis

1-Allyl-4-hydroxy-2,2-dioxo-N-(4-methoxyphenyl)-1H-2λ6,1-benzothiazine-3-carboxamide: polymorphic transition due to grinding with the loss of the biological activity

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Biological properties of two enantiomorphic forms ofN-(2,6-dimethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxamide, a structural analogue of piroxicam

1-Allyl-4-hydroxy-2,2-dioxo-N-(4-methoxyphenyl)-1H-2λ⁶,1-benzothiazine-3-carboxamide: polymorphic transition due to grinding with the loss of the biological activity