Synthesis and bioevaluation of new pyranophenothiazine derivatives

Abstract

Until now, tuberculosis is always a dangerous infectious disease. Because of the enlargement of multidrug-resistant strains (MDR-TB), the need of new drugs becomes more important. Fusing of 2 pharmacophores (phenothiazine and benzopyran), we intend to synthesize some new pyranophenothiazine derivatives, and evaluate their antituberculosis activities. The designed compounds were prepared using conventional synthetic methods with all PA chemical agents (from Merk, TCI, Sigma). The structure of all synthesized compounds had been confirmed by analysis of NMR and MS spectra. Antimycobacterial activity of the synthesized compounds on Mycobacterium bovis BCG (or on the virulent strain Mycobacterium tuberculosis H37Rv for the most promising compounds) had been determined using the Microdilution resazurin assay. 2 compounds 8 and 9 were obtained by Claisen rearrangement of intermediate dimethylpropargyl ether. The sulfoxide and (+)cis-diol sulfoxide derivatives were obtained by oxydation, and the dihydro-derivatives -by reduction of the leader compounds. The anti-tuberculosis activities of 12 synthesized compounds were evaluated. Only the leading compound of linear structure (pyrano[b]phenothiazine) and 2 non-sulfoxide derivatives of angular structure (pyrano[a]phenothiazine) exhibited a mild inhibiting activity on the tested tuberculosis source. 12 new pyrano-phenothiazine compounds have been prepared and bioevaluated. The results showed that 3 compounds exhibited a mild inhibiting activity on the tested tuberculosis source. These structural requirements will be taken into account for the design of further analogues in pyranophenothiazine series.