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 , 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 -acylhydrazones. To amplify the best binders, we employed anti-infective target 4-diphosphocytidyl-2-methyl-d-erythritol kinase (IspE) from (). 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 -acylhydrazones, we synthesized 12 of them, revealing several new starting points for the development of IspE inhibitors as antibacterial agents.
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| http://dx.doi.org/10.1021/acsomega.4c05537 | DOI Listing |
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