Diseño, síntesis y estudio de 1,3,4-tiadiazoles como inhibidores de la enoil-ACP-reductasa (InhA) de M. tuberculosis

Resumen

The work described in this report has been developed in the DDW (Diseases of the Developing World) GlaxoSmithKline center in Tres Cantos (Madrid) under the direction of Dra. Julia Castro Pichel and Dra. Esther Fernández Velando. This work was done in collaboration with the GATB (Global Alliance for Tuberculosis) organization. The main objective of this research program has been to identify new InhA inhibitors within the family of thiadiazoles, these molecules should be active against TB-MDR strains and TB-XDR type. These new compounds would be administered in combination, replacing one or more of the drugs used in current regimens of directly observed therapy. The identified compounds should be able to be administered orally, well tolerated and show low generation frequency of resistance. In the development of this research project the design and synthesis of new modifications in the overall structure of GSK1, hit of the thiadiazole series, have been carried out with the aim of improving the enzymatic activity as well as the whole cell potency and physicochemical profile of the new compounds. Molecules result of the proposed modifications were evaluated in the appropriate biological studies, assessing their potential as anti-TB drugs. After the biological evaluation exercise and SAR study of the series compound 106 was identified as the most promising structure. This compound has been progressed to the Pre-Candidate and is currently in combination studies, contributing that way to the identification of a novel direct inhibitor of the well validated enzyme InhA.