MatviiukTetiana . Design, synthesis and evaluation of biological activity of 1,3-disubstituted pyrrolidine-2,5-diones as potential antituberculosis agents

The thesis is devoted to the synthesis of 1,3-disubstituted pyrrolidine-2,5-diones and evaluation of their inhibitory activity against InhA protein and Mycobacterium tuberculosis. In particular new catalytic condition of the Michael reaction were found. Lewis acids (such as: AlCl3, ZnCl2 and LiClO4) are developed as efficient catalysts for series of conjugate addition of maleimides to nucleophilic heterocycles. New conditions enabled efficient synthesis of 3-heteryl substituted pyrrolidine-2,5-diones. Double-conjugate addition products were obtained in the reactions with 2-aminopyridines and 2-aminothiazoles under mild conditions in presence of catalytic amount of lithium perchlorate. The possible mechanism of the formation of desired products is proposed. The structure of new potential inhibitors of InhA protein were designed using molecular modeling and in silico screening tools. Key structure of 3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione identified from the docking studies was synthesized in two different approaches. The series of N-substituted derivatives of this scaffold with divers substituents were synthesized to identify structure-activity relationships. Moreover the series of b-amides of 2-(9H-fluoren-9-yl)-succinic acid were also synthesized. Identified and optimized condition of reduction of 3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione using borane dimethyl sulfide complex have enabled production of two desired products in one reaction with quantitative yields. The series of corresponding compounds with pyrrolidone and pyrrolidine ring were obtained. The reactions of 3-(9H-fluoren-9-yl)pyrrolidine-2,5-dione and its N-substituted derivatives with lithium aluminium hydride were investigated. Tandem reduction/oxidation of pyrrolidine-2,5-dione and fluorenyl rings was performed using 4 equivalents of LiAlH4 under air, affording the series of corresponding 9-hydroxy fluorenyl derivatives in good yields. Possible mechanism of oxidation of 9-substituted fluorenyl compounds is proposed. Three families of synthesized compounds were evaluated in vitro for the inhibition of InhA enzyme and M.tuberculosis growth. Almost of synthesized compounds have shown good inhibitory activity against InhA and/or Mycobacterium tuberculosis (H37Rv strain). Some of evaluated compounds could represent new leads for the development of drug candidates.