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

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.