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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

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Department of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska st., 61002 Kharkiv, Ukraine
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STC “Institute for Single Crystals”, National Academy of Sciences of Ukraine, 60 Nauki ave., 61001 Kharkiv, Ukraine
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Department of Inorganic Chemistry, V. N. Karazin Kharkiv National University, 4 Svobody sq., 61077 Kharkiv, Ukraine
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Laboratory of Viral Infection, State Institution “I. Mechnikov Institute of Microbiology and Immunology National Academy of Medical Sciences of Ukraine”, 14-16 Pushkinska st., 61057 Kharkiv, Ukraine
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Department of Pharmacology, N. I. Pirogov Vinnitsa National Medical University, 56 Pirogov st., 21018 Vinnitsa, Ukraine
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Author to whom correspondence should be addressed.
Sci. Pharm. 2020, 88(1), 10; https://doi.org/10.3390/scipharm88010010
Received: 3 February 2020 / Revised: 16 February 2020 / Accepted: 21 February 2020 / Published: 2 March 2020
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. View Full-Text
Keywords: 2,1-benzothiazine; esters; 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid; crystal structure; molecular conformation; analgesic activity 2,1-benzothiazine; esters; 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid; crystal structure; molecular conformation; analgesic activity
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Ukrainets, I.V.; Petrushova, L.A.; Shishkina, S.V.; Sidorenko, L.V.; Alekseeva, T.V.; Torianyk, I.I.; Davidenko, A.A. 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. Sci. Pharm. 2020, 88, 10.

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