Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis.

The neuroleptic drug thioridazine has been recently repositioned as possible anti-tubercular drug. Thioridazine showed anti-tubercular activity against drug resistant mycobacteria but it is endowed with adverse side effects. A small library of thioridazine derivatives has been designed through the replacement of the piperidine and phenothiazine moieties, with the aim to improve the anti-tubercular activity and to reduce the cytotoxic effects. Among the resulting compounds, the indole derivative 12e showed an antimycobacterial activity significantly better than thioridazine and a cytotoxicity 15-fold lower.

Rational Design and Synthesis of Thioridazine Analogues as Enhancers of the Antituberculosis Therapy.

Tuberculosis, caused by Mycobacterium tuberculosis, is still one of the leading infectious diseases globally. Therefore, novel approaches are needed to face this disease. Efflux pumps are known to contribute to the emergence of M. tuberculosis drug resistance. Thioridazine has shown good anti-TB properties both in vitro and in vivo, likely due to its capacity to inhibit efflux mechanisms. Here we report the design and synthesis of a number of putative efflux inhibitors inspired by the structure of thioridazine. Compounds were evaluated for their in vitro and ex vivo activity against M. tuberculosis H37Rv. Compared to the parent molecule, some of the compounds synthesized showed higher efflux inhibitory capacity, less cytotoxicity, and a remarkable synergistic effect with anti-TB drugs both in vitro and in human macrophages, demonstrating their potential to be used as coadjuvants for the treatment of tuberculosis.

Synthesis, isolation, and characterization of two stereoisomeric ring sulfoxides of thioridazine.

A selective oxidation of thioridazine to give exclusively its ring sulfoxides and a separation of the resulting products as diastereoisomeric pairs of enantiomers (DL, LD and DD, LL) are reported. These pairs were characterized by TLC, high-performance liquid chromatographic, IR, UV, 1H-NMR, 13C-NMR, GC-MS, and elemental analyses, and by reduction to thioridazine by lithium aluminum hydride. Structural data for the separated diastereoisomeric pairs or their nitric acid salts were obtained from NMR and IR studies. Gram quantities of each of the two diastereoisomeric pairs of enantiomers were isolated in better than 99% purity.

Synthesis, characterization and electrical properties of peripherally tetra-aldazine substituted novel metal free phthalocyanine and its zinc(II) and nickel(II) complexes.

The novel phthalonitrile containing azine segment and its corresponding tetra aldazine substituted metal free- and metallo-phthalocyanines (Zn(II) and Ni(II)) were synthesized and characterized by IR, (1)H NMR, Mass, UV-Vis spectroscopy and elemental analysis and addition to these techniques for substituted phthalonitrile (13)C NMR have been used. In addition, dc and ac electrical properties of the films of these novel phthalocyanines were investigated as a function of temperature (295-523 K) and frequency (40-10(5)Hz). Activation energy values of the films of the phthalocyanines were calculated from straight portions of the Arrhenius plot (lnσ(dc)-1/T curves) as 0.70 eV, 0.93 eV and 0.91 eV for the films of metal free, nickel- and zinc-phthalocyanines, respectively. From impedance spectroscopy measurements, it is observed that bulk resistance decreases with increasing temperature indicating semiconductor property.