LAUSR

Schistosomiasis is a prevalent yet neglected tropical parasitic disease caused by the Schistosoma genus of blood flukes. Praziquantel is the only currently available treatment, hence drug resistance poses a major threat. Recently, histone deacetylase 8 (HDAC8) selective inhibitors have been proposed as a viable treatment for schistosomiasis. Herein, we report the phenotypic screening of a focused library of small molecules of varying HDAC isozyme‐inhibition profiles, including eight HDAC8 inhibitors with >10‐fold selectivity in comparable functional inhibition assays and IC50 values against HDAC8<100 nM. HDAC8‐selective inhibitors showed the lowest potency against Schistosoma mansoni newly transformed schistosomula (NTS). Pan‐HDAC inhibitors MMH258, MMH259, and MMH373, as assessed by functional inhibition assays, with minimal or no‐observed hHDAC8 and SmHDAC8 activities, were active against both NTS (MMH258, IC50=1.5 μM; MMH259, IC50=2.3 μM) and adult S. mansoni (MMH258, IC50=2.1 μM; MMH373, IC50=3.4 μM). Our results indicate that neither hHDAC8 nor SmHDAC8 activity were directly correlated to their NTS and adult S. mansoni activities.