Synthesis of new derivatives of 8-trifluoromethylquinobenzothiazine

Phenothiazine is an important heterocyclic scaffold present in numerous biologically active compounds. Its derivatives exhibit a broad spectrum of pharmacological activities, including anticancer, antibacterial, antiviral, antifungal and anti-inflammatory effects. Due to their diverse biological properties, phenothiazine derivatives have been the subject of our previous studies, particularly in the search for compounds with antiproliferative and antibacterial activity. The present study is a continuation of our previous research on 8-trifluoromethylquinobenzothiazine derivatives. The aim of this study was to synthesize new derivatives of 8-trifluoromethylquinobenzothiazine for further investigation of their biological properties. The synthesis was carried out using two synthetic pathways. The first path consisted of reaction between 8-trifluoromethylquinobenzothiazine and N-(4-bromobutyl)phthalimide that led to obtaining butylphthalimide derivative. Then that derivative underwent hydrolysis with hydrazine hydrate in ethanol to 6-aminobutyl-8-trifluoromethylquinobenzothiazine. The 6-aminobutyl-8-trifluoromethylquinobenzothiazine was use to synthesize six different derivatives: acetylaminobutyl, metanosulfonylbutyl, p-tolylsulfonylbutyl, chloroethylureidobutyl, p-trifluoromethylureidobutyl and p-tolylsulfonylureidobutyl. The second path included reaction between 8-trifluoromethylquinobenzothiazine and 1-bromo-4-chlorobutane that resulted in getting chlorobutyl derivative. The chlorobutyl derivative was then use to synthesize four different derivatives: 1-methylpiperazinylbutyl, 1-(2-hydroxyethyl)piperazinylbutyl, 1-phenylpiperazinylbutyl and 1-pyridinylpiperazinylbutyl. The structure of all synthesized compounds was confirmed by spectroscopic analysis such as ¹H NMR, ¹³C NMR, ¹⁹F NMR and mass spectrometry ESI HRMS. The applied synthetic approaches proved effective for the preparation of new 8-trifluoromethylquinobenzothiazine derivatives and provided a series of compounds suitable for further evaluation of their biological activity.