Êtes-vous un étudiant de l'EPFL à la recherche d'un projet de semestre?
Travaillez avec nous sur des projets en science des données et en visualisation, et déployez votre projet sous forme d'application sur GraphSearch.
We report the discovery of benzothiazoles, a novel anti-mycobacterial series, identified from a whole cell based screening campaign. Benzothiazoles exert their bactericidal activity against Mycobacterium tuberculosis (Mtb) through potent inhibition of decaprenylphosphoryl-beta-D-ribose 2'-oxidase (DprE1), the key enzyme involved in arabinogalactan synthesis. Specific target linkage and mode of binding were established using co-crystallization and protein mass spectrometry studies. Most importantly, the current study provides insights on the utilization of systematic medicinal chemistry approaches to mitigate safety liabilities while improving potency during progression from an initial genotoxic hit, the benzothiazole N-oxides (BTOs) to the lead-like AMES negative, crowded benzothiazoles (cBTs). These findings offer opportunities for development of safe clinical candidates against tuberculosis. The design strategy adopted could find potential application in discovery of safe drugs in other therapy areas too. (c) 2015 Elsevier Ltd. All rights reserved.
Chargement
Chargement
Chargement
Chargement
Chargement
Stewart Cole, Neeraj Dhar, Ruben Hartkoorn, Claudia Sala, Ming Zhang
Joao Pedro De Almeida Neres, Neeraj Dhar, John McKinney, François Signorino-Gelo
Stewart Cole, Joao Pedro De Almeida Neres, Neeraj Dhar, Ruben Hartkoorn, Gaëlle Séraphine Kolly, Florence Pojer