Structure‐Based Design, Synthesis, and Biological Evaluation of Triazole‐Based smHDAC8 Inhibitors

Abstract

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‐1H‐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‐1H‐1,2,3‐triazole‐4‐carboxamide), a nanomolar smHDAC8 inhibitor (IC50=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.

Strategies To Design Selective Histone Deacetylase Inhibitors

“…For instance, Kalinin et al. designed and prepared a series of S. mansoni HDAC8 inhibitors with a hydroxamic acid ZBG and a triazole linker expected to target the unique S. mansoni HDAC8 amino acid residue H292 [77c] . Compound 42 (Figure 3), which similar to compounds 38 – 40 only bears a phenyl cap group, exhibited a slightly different selectivity pattern than observed to the analogous compounds 38 – 40 .…”

“…Kalinin et al. applied structure‐based design to optimize their S. mansoni HDAC8‐selective inhibitor compound 42 (Figure 3) consisting of a hydroxamic acid ZBG, a triazole linker and a phenyl cap group by adding different aromatic substituents to the ortho ‐position of the phenyl cap group [77c] . Molecular docking studies predicted that such a substituent would act as an SP‐group and would occupy the side pocket in HDAC8 further improving the activity and the selectivity profile.…”

The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs

“…These characteristics are similar to the previously reported for the crystal structure of HDAC8 from S. mansoni [26] and have been applied to the structure-based design of selective inhibitors. In this way, a series of mercaptoacetamide [29], benzhydroxamate [30,31], cinnamic acid [32] and triazole [33] derivatives were synthesized, among others. Several of these compounds have shown high selective activities for HDAC8 from S. mansoni (SmHDAC8) or Homo sapiens (HsHDAC8) over the major human HDAC isoforms (HDAC1 and HDAC6), displaying low nanomolar activity against both HDAC8s.…”

“…A number of these compounds are more active on SmHDAC8 than on HsHDAC8. Furthermore, several SmHDAC8 inhibitors have shown to be effective against both adult and larval schistosomes, and have displayed limited toxicity to human cell lines [29][30][31][32][33]. The conservation of these characteristics in cestode HDAC8s suggests that selective SmHDAC8 inhibitors should be active against cestode HDAC8s and potentially novel anthelmintic drugs against these parasites.…”

“…mansoni [ 26 ] and have been applied to the structure-based design of selective inhibitors. In this way, a series of mercaptoacetamide [ 29 ], benzhydroxamate [ 30 , 31 ], cinnamic acid [ 32 ] and triazole [ 33 ] derivatives were synthesized, among others. Several of these compounds have shown high selective activities for HDAC8 from S .…”