Target-Directed\nDynamic Combinatorial Chemistry Affords\nBinders of <i>Mycobacterium tuberculosis</i> IspE

In the search for new antitubercular compounds, we leveraged\ntarget-directed\ndynamic combinatorial chemistry (tdDCC) as an efficient hit-identification\nmethod. In tdDCC, the target selects its own binders from a dynamic\nlibrary generated <i>in situ</i>, reducing the number of\ncompounds that require synthesis and evaluation. We combined a total\nof 12 hydrazides and six aldehydes to generate 72 structurally diverse <i>N</i>-acylhydrazones. To amplify the best binders, we employed\nanti-infective target 4-diphosphocytidyl-2<i>C</i>-methyl-d-erythritol kinase (IspE) from <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>). We successfully validated the use of tdDCC\nas hit-identification method for IspE and optimized the analysis of\ntdDCC hit determination. From the 72 possible <i>N</i>-acylhydrazones,\nwe synthesized 12 of them, revealing several new starting points for\nthe development of IspE inhibitors as antibacterial agents.