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 4-diphosphocytidyl-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 N-acylhydrazones, we synthesized 12 of them, revealing several new starting points for the development of IspE inhibitors as antibacterial agents.
Braun-Cornejo, M., Ornago, C., Sonawane, V., Haupenthal, J., Kany, A.M., Diamanti, E., et al. (2024). Target-Directed Dynamic Combinatorial Chemistry Affords Binders of Mycobacterium tuberculosis IspE. ACS OMEGA, 9(36), 38160-38168 [10.1021/acsomega.4c05537].
Target-Directed Dynamic Combinatorial Chemistry Affords Binders of Mycobacterium tuberculosis IspE
Diamanti, Eleonora;
2024
Abstract
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 4-diphosphocytidyl-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 N-acylhydrazones, we synthesized 12 of them, revealing several new starting points for the development of IspE inhibitors as antibacterial agents.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.