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Structure‐Based Design, Synthesis, and Biological Evaluation of Triazole‐Based smHDAC8 Inhibitors
Author(s) -
Kalinin Dmitrii V.,
Jana Sunit K.,
Pfafenrot Maxim,
Chakrabarti Alokta,
Melesina Jelena,
Shaik Tajith B.,
Lancelot Julien,
Pierce Raymond J.,
Sippl Wolfgang,
Romier Christophe,
Jung Manfred,
Holl Ralph
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900583
Subject(s) - chemistry , triazole , selectivity , stereochemistry , drug discovery , carboxamide , structure–activity relationship , virtual screening , schistosoma , antiparasitic , schistosomiasis , schistosoma mansoni , biochemistry , biology , medicine , in vitro , immunology , helminths , organic chemistry , pathology , catalysis
Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma , which affects over 200 million people worldwide and leads to at least 300,000 deaths every year. In this study, initial screening revealed the triazole‐based hydroxamate 2 b ( N ‐hydroxy‐1‐phenyl‐1 H ‐1,2,3‐triazole‐4‐carboxamide) exhibiting potent inhibitory activity toward the novel antiparasitic target Schistosoma mansoni histone deacetylase 8 (smHDAC8) and promising selectivity over the major human HDACs. Subsequent crystallographic studies of the 2 b /smHDAC8 complex revealed key interactions between the inhibitor and the enzyme's active site, thus explaining the unique selectivity profile of the inhibitor. Further chemical modifications of 2 b led to the discovery of 4‐fluorophenoxy derivative 21 (1‐[5‐chloro‐2‐(4‐fluorophenoxy)phenyl]‐ N ‐hydroxy‐1 H ‐1,2,3‐triazole‐4‐carboxamide), a nanomolar smHDAC8 inhibitor (IC 50 =0.5 μM), exceeding the smHDAC8 inhibitory activity of 2 b and SAHA (vorinostat), while exhibiting an improved selectivity profile over the investigated human HDACs. Collectively, this study reveals specific interactions between smHDAC8 and the synthesized triazole‐based inhibitors and demonstrates that these small molecules represent promising lead structures, which could be further developed in the search for novel drugs for the treatment of schistosomiasis.