SYNTHESIS AND ANTIEXUDATIVE ACTIVITY OF N-ОXIDES 4-PYRIDINYLOXYSUBSTITUTED (BENZO)IMIDAZO[2,1-b][1,3]THIAZINES

Abstract

The imidazo[2,1-b][1,3]thiazine nucleus, as well as the pyridine-N-oxide fragment, are pharmacophore groups that have received much attention from researchers. That is why the combination of these scaffolds in the structure of a single molecule seems to be quite attractive from chemical and biological point of view. Synthetically available 4-pyridinyloxy-substituted (benzo)imidazo[2,1-b]thiazines were used as precursors to obtain previously unknown (benzo)imidazo[2,1-b][1,3]thiazin-6-yloxypyridine 1-oxides. It was found that the oxidation of the latter with m-chlorobenzoic acid under mild reaction conditions using dichloromethane as a solvent at room temperature proceeds smoothly and selectively to obtain only the target products. The composition and structure of the synthesized pyridine-N-oxides are unambiguously confirmed by complex physicochemical analysis, particularly by 1H and 13C NMR spectroscopy, chromato-mass spectrometry, as well as elemental analysis data. The antiexudative activity of (benz)imidazo[2,1-b][1,3]thiazin-6-yloxypyridine 1-oxides was studied in vivo in a model of carrageenan-induced paw edema in white outbred male rats. The development of edema was considered from increasing the volume of the paw 4 hours after the introduction of carrageenan. Quantitative assessment of antiexudative activity was performed by the degree of reduction of rat paw edema, and the rate of suppression of the inflammatory process was calculated. Performed bioscreening showed that the synthesized pyridine-N-oxides are characterized by weak anti-inflammatory activity, and only 2-chloro-4-[(2,3-diphenyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-6-yl)oxy]pyridine 1-oxide 2a has moderate antiexudative effect with of inflammatory inhibition rate of 31.9%. This compound is thus of interest for further structural modification in order to obtain potential non-steroidal anti-inflammatory agents. It is important to note that the presence in the structure of the synthesized derivatives 2a-e of N-oxide fragment is very promising for the design of anti-inflammatory agents, which are characterized by the absence of side effects caused by inhibition of cyclooxygenase-1.