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-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.
Highlights
In the case of observable pharmacological effects caused by enantiomers and racemates formed thereof, this explanation may be quite insufficient. This is exactly the situation we encountered when studying N-(1-arylethyl)-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides, which are the object of this message
More attention has been paid to the development of modern technologies of asymmetric synthesis, which would allow to immediately obtain biologically active substances with the known-good configuration of chiral centers [28,29,30,31]
The chiral fragment, as a rule, is introduced into the molecule at the final stage of the synthetic scheme, which allows for minimizing the risk of possible racemization. This strategy was implemented in the synthesis of the target objects in the present study: the previously formed bicyclic 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic
Summary
The number of unique properties, the study which constitutes the range of of scientific interests of synthetic appearance of at least one asymmetric carbon atom in the molecule provides the substance with a chemists, analysts, spectroscopists, optics, crystallographers, and various other scientists. Different, and sometimes directly opposite, physiological properties [2], or one of the isomers would It is within the realm of possibility that enantiomers would exhibit completely different, and sometimes prove itself as unambiguously harmful or even dangerous [10]. In the case of observable pharmacological effects caused by enantiomers and racemates formed thereof, this explanation may be quite insufficient. This is exactly the situation we encountered when studying N-(1-arylethyl)-4-methyl-2,2-dioxo-1H-2λ6 ,1-benzothiazine-3-carboxamides, which are the object of this message
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