Structure-Based Design and Synthesis of Novel Inhibitors Targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis

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• 作者：Tino Heimburg ; Alokta Chakrabarti ; Julien Lancelot ; Martin Marek ; Jelena Melesina ; Alexander-Thomas Hauser ; Tajith B. Shaik ; Sylvie Duclaud ; Dina Robaa ; Frank Erdmann ; Matthias Schmidt ; Christophe Romier ; Raymond J. Pierce ; Manfred Jung ; Wolfgang Sippl
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 24, 2016
• 年：2016
• 卷：59
• 期：6
• 页码：2423-2435
• 全文大小：806K
• ISSN：1520-4804

文摘

Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, a series of new benzohydroxamates were prepared as potent inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by these 3-amidobenzohydroxamates. The newly designed inhibitors were evaluated in screens for enzyme inhibitory activity against schistosome and human HDACs. Twenty-seven compounds were found to be active in the nanomolar range, and some of them showed selectivity toward smHDAC8 over the major human HDACs (1 and 6). The active benzohydroxamates were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Four of these showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.