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

• Published in: Scientia pharmaceutica Vol. 87; no. 2; pp. 10 - 20
• Main Authors: Ukrainets, Igor V., Hamza, Ganna M., Burian, Anna A., Voloshchuk, Natali I., Malchenko, Oxana V., Shishkina, Svitlana V., Danylova, Irina A., Sim, Galina
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01-04-2019
• Subjects: 2,1-benzothiazine; 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylamide; analgesic activity; Analgesics; anti-inflammatory action; Biological activity; Carbon; Chemistry; chiral switches, crystal structure; Chromatography; Crystal structure; Drugs; molecular conformation; NMR; Nuclear magnetic resonance; Pharmaceutical industry; Researchers; United Kingdom > UK; United States > US; Switzerland
• ISSN: 2218-0532; 0036-8709; 2218-0532
• DOI: 10.3390/scipharm87020010

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-2λ6,1-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-2λ6,1-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.