Sulfones of Pyridinyloxy-Substituted Imidazo[2,1-b][1,3]thiazines: Synthesis, Anti-Inflammatory Activity Evaluation In Vivo and Docking Studies

Abstract

Background: Heterocyclic sulfone-bearing small molecules are particularly important objects in medicinal chemistry. Structure-diversified pyridinyloxy-substituted imidazo[2,1-b][1,3]thiazines are characterized with satisfactory drug-like parameters and possess significant anti-inflammatory effect in in vivo studies. Objective: Oxidation of a series of 6-(2-pyridinyloxy) imidazo[2,1-b][1,3]thiazines under the action of m-chloroperbenzoic acid with a view to anti-inflammatory activity enhancement and structure optimization. Methods: A series of appropriate sulfones was synthesized by the action of m-chloroperbenzoic acid on 6-[(pyridin-2-yl)oxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazines. The structure of the synthesized products was confirmed by 1H, 13C NMR, and LC-MS spectra. In vivo anti-inflammatory activity was studied using carrageenin model of inflammatory oedema on white rats. ADMET parameters of compounds were evaluated in silico using AdmetSAR. For the most active compounds, docking studies to COX-1,2, 5-LOX and FLAP were performed. Results: Results: It was found that transformation to sulfones could be achieved by soft oxidation at room temperature during 48 h using the 3-fold excess of oxidant in presence of sodium hydrogen phosphate. Anti-inflammatory activity screening results revealed that all synthesized sulfones showed significant anti-exudative action with inflammation inhibition index in the range 37.7 - 48.1%. The compound 2i was found the most active in the experiment, and its activity was equal to the reference drug effect; it also possesses satisfactory ADMET parameters and high energy of binding to 5-LOX and FLAP. Conclusion: The synthesized sulfone 2i is of an interest for in-depth studies and further design of new potential non-steroidal anti-inflammatory agents.