Synthesis and biological evaluation as well as in silico studies of arylpiperazine-1,2-benzothiazine derivatives as novel anti-inflammatory agents

Novel arylpiperazine-1,2-benzothiazine derivatives have been designed and synthesized as potential antiinflammatory agents. Their structure and properties have been studied using spectroscopic techniques (H-1 NMR, C-13 NMR, FT-IR), MS, elemental analyses, and single-crystal X-ray diffraction (SCXRD, for compound 7b). This study aimed to evaluate the inhibitory activity of new derivatives against both cyclooxygenase isoforms COX-1 and COX-2 due to the similarity of new compounds to oxicams drugs from the NSAIDs group. All new compounds were divided into two series - A and B - with a different linker between thiazine and piperazines nitrogens. Series A included the three-carbon aliphatic linker and series B - two-carbon with a carbonyl group. According to in vitro and molecular docking studies all new compounds exhibited cyclooxygenase inhibitory activity. The series of A compounds included COX-1 inhibitors only. In contrast, the B series showed inhibition of both COX-1 and COX-2, which suggested the importance of the acetoxy linker for COX-2 inhibition. Moreover, the most selective compound 7b, towards COX-2, was non-toxic for the normal human cell line (in concentration of 10 mu M) comparable to reference drug meloxicam. Additionally, investigation of influence on model membranes confirmed the ability of the compound 7b to penetrate lipid bilayers which seemed to be important to the influence with membrane protein-cyclooxygenase.

Automated summary

Novel arylpiperazine-1,2-benzothiazine derivatives were designed and synthesized as potential anti-inflammatory agents, with one compound showing good inhibitory activity against COX-2 and being non-toxic to normal human cells. Additionally, the study confirmed the ability of the compound to penetrate lipid bilayers, suggesting its importance in interacting with membrane protein-cyclooxygenase.