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Target-Directed Dynamic Combinatorial Chemistry Affords Binders of Mycobacterium tuberculosis IspE

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Braun-Cornejo, Maria | Ornago, Camilla | Sonawane, Vidhisha | Haupenthal, Jörg | Kany, Andreas, M | Diamanti, Eleonora | Jézéquel, Gwenaëlle | Reiling, Norbert | Blankenfeldt, Wulf | Maas, Peter | Hirsch, Anna, K H

Edité par CCSD ; ACS Publications -

International audience. In the search for new antitubercular compounds, we leveraged target-directed dynamic combinatorial chemistry (tdDCC) as an efficient hit-identification method. In tdDCC, the target selects its own binders from a dynamic library generated in situ, reducing the number of compounds that require synthesis and evaluation. We combined a total of 12 hydrazides and six aldehydes to generate 72 structurally diverse N-acylhydrazones. To amplify the best binders, we employed anti-infective target 4diphosphocytidyl-2C-methyl-D-erythritol kinase (IspE) from Mycobacterium tuberculosis (Mtb). We successfully validated the use of tdDCC as hit-identification method for IspE and optimized the analysis of tdDCC hit determination. From the 72 possible Nacylhydrazones, we synthesized 12 of them, revealing several new starting points for the development of IspE inhibitors as antibacterial agents.

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