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The Crystal Structure of N-(1-Arylethyl)-4-methyl- 2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides as the Factor Determining Biological Activity Thereof

1
Department of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska st., 61002 Kharkiv, Ukraine
2
Department of Pharmacology, N.I. Pirogov Vinnitsa National Medical University, 56 Pirogov st., 21018 Vinnitsa, Ukraine
3
STC “Institute for Single Crystals”, National Academy of Sciences of Ukraine, 60 Nauki ave., 61001 Kharkiv, Ukraine
4
Department of Inorganic Chemistry, V.N. Karazin Kharkiv National University, 4 Svobody sq., 61077 Kharkiv, Ukraine
5
Department of Pharmaceutical Chemistry, Far Eastern State Medical University, 35 Murav’eva-Amurskogo st., 680000 Khabarovsk, Russia
*
Author to whom correspondence should be addressed.
Sci. Pharm. 2019, 87(2), 10; https://doi.org/10.3390/scipharm87020010
Received: 27 February 2019 / Revised: 3 April 2019 / Accepted: 4 April 2019 / Published: 19 April 2019
(This article belongs to the Special Issue Heterocyclic Chemistry in Drug Design)
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Abstract

In order to detect new structural and biological patterns in a series of hetaryl-3-carboxylic acid derivatives, the optically pure (S)- and (R)-enantiomers of N-(1-arylethyl)-4-methyl- 2,2-dioxo-1H-6,1-benzothiazine-3-carboxamides, their true racemates, and mechanical racemic mixtures have been synthesized in independent ways. The particular features of the 1Н- and 13С-NMR spectra of all synthesized substances, liquid chromato-mass spectrometric behavior thereof under electrospray ionization conditions, and also the results of polarimetric and X-ray diffraction studies have been discussed. Pharmacological screening on a model of carrageenan inflammation has found a clear relationship between the spatial structure of the studied objects and biological activity thereof. Enantiomers with chiral centers having (S)-configuration showed weak inhibition of pain and inflammatory reactions, while their mirror (R)-isomers exhibited very powerful analgesic and antiphlogistic properties under the same conditions, with the level of specific activity exceeding that of Lornoxicam and Diclofenac. Taking obtained data into account, a noticeable decrease in the activity of mechanical racemic mixtures, consisting of one-half of the “wrong” (S)-enantiomers, is quite natural. The true racemate of N-(1-phenylethyl)-amide proved itself in a similar way, while 4-methoxy-substituted analog thereof stood out against this background with unexpectedly high analgesic and anti-inflammatory activities. A comparative analysis of X-ray diffraction data has found that crystalline and molecular structure of racemic N-[1-(4-methoxyphenyl)ethyl]-4-methyl-2,2-dioxo-1H-6,1-benzothiazine-3-carboxamide is completely different from that of the original enantiomers and, moreover, very unusual for racemates. Obviously, it is the factor determining the unique character of the biological effects of the said substance. View Full-Text
Keywords: 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylamide; 2,1-benzothiazine; chiral switches, crystal structure; molecular conformation; analgesic activity; anti-inflammatory action 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylamide; 2,1-benzothiazine; chiral switches, crystal structure; molecular conformation; analgesic activity; anti-inflammatory action
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Ukrainets, I.V.; Hamza, G.M.; Burian, A.A.; Voloshchuk, N.I.; Malchenko, O.V.; Shishkina, S.V.; Danylova, I.A.; Sim, G. The Crystal Structure of N-(1-Arylethyl)-4-methyl- 2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides as the Factor Determining Biological Activity Thereof. Sci. Pharm. 2019, 87, 10.

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