Design,synthesis and neuroprotective effect of thiol HDAC6 inhibitors containing pyrazolformamide
Computer-aided drug design methods were used to connect the benzene ring with the pyrazole ring via an aliphatic carbon chain in the lead compounds based on the thiols-containing HDAC inhibitors B-4 and E-15k.This created an enlarged tricyclic structure to fit the active site pocket of the HDAC6 protein.On this structural basis,various substituents were introduced to synthesize a series of novel HDAC6 inhibitors containing a pyrazolecarboxamide structure.A total of 14 compounds were synthesized,and their structures were confirmed by mass spectrometry and nuclear magnetic resonance spectroscopy.The target inhibitory activity and neuroprotective effects of the synthesized target compounds were evaluated in vitro.The experimental results showed that compounds 17a-17c exhibited potent inhibitory activity and selectivity towards HDAC6.Additionally,compound 17b showed some neuroprotective effects in vitro.
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