Title:Sulfones of Pyridinyloxy-Substituted Imidazo[2,1-b][1,3]thiazines: Synthesis, Anti-Inflammatory Activity Evaluation In Vivo and Docking Studies
Volume: 20
Issue: 11
Author(s): Nataliia Slyvka*, Lesya Saliyeva, Serhii Holota, Dmytro Khyluk, Victor Tkachuk and Mykhailo Vovk
Affiliation:
- Department of Organic Chemistry and Pharmacy, Lesya Ukrainka Volyn National University, Lutsk, Ukraine
Keywords:
Imidazo[2, 1-b][1, 3]thiazines, m-chloroperbenzoic acid, oxidation, drug-likeness, anti-inflammatory activity, docking.
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 by satisfactory drug-like parameters and possess significant anti-inflammatory effects 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: It was found that transformation to sulfones could be achieved by soft oxidation at room temperature
for 48 h using the 3-fold excess of oxidant in the presence of sodium hydrogen phosphate. Antiinflammatory
activity screening results revealed that all synthesized sulfones showed significant antiexudative
action with inflammation inhibition index in the range of 37.7 - 48.1%. The compound 2i was
found to be 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 interest for in-depth studies and further design of new potential
non-steroidal anti-inflammatory agents.
