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
Specs Compound Handling, B.V., Bleiswijkseweg 55, 2712 PB Zoetermeer, The Netherlands.
Saarland University, Department of Pharmacy, Campus Building E8.1, 66123 Saarbrücken, Germany.
ACS Omega. 2024 Aug 29;9(36):38160-38168. doi: 10.1021/acsomega.4c05537. eCollection 2024 Sep 10.
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.
在寻找新型抗结核化合物的过程中，我们利用靶向动态组合化学（tdDCC）作为一种高效的命中化合物鉴定方法。在tdDCC中，靶点从生成的动态库中选择自身的结合物，减少了需要合成和评估的化合物数量。我们总共将12种酰肼和6种醛结合，生成了72种结构多样的酰腙。为了放大最佳结合物，我们采用了来自[具体来源未给出]的抗感染靶点4-二磷酸胞苷-2-甲基-D-赤藓糖醇激酶（IspE）。我们成功验证了tdDCC作为IspE命中化合物鉴定方法的实用性，并优化了tdDCC命中化合物确定的分析方法。从72种可能的酰腙中，我们合成了其中12种，揭示了开发作为抗菌剂的IspE抑制剂的几个新起点。
