Isophthalic Acid‐Based HDAC Inhibitors as Potent Inhibitors of HDAC8 from Schistosoma mansoni

Abstract

Schistosoma mansoni histone deacetylase 8 (SmHDAC8) has been recently identified as a new potential target for the treatment of schistosomiasis. A series of newly designed and synthesized alkoxyamide-based and hydrazide-based HDAC inhibitors were tested for inhibitory activity against SmHDAC8 and human HDACs 1, 6, and 8. The front runner compounds showed submicromolar activity against SmHDAC8 and modest preference for SmHDAC8 over its human orthologue hHDAC8. Docking studies provided insights into the putative binding mode in SmHDAC8 and allowed rationalization of the observed selectivity profile.

Synthesis, Crystallization Studies, and in vitro Characterization of Cinnamic Acid Derivatives as SmHDAC8 Inhibitors for the Treatment of Schistosomiasis

“…Chemical structures and IC 50 values of previously reported inhibitors tested against SmHDAC8. [23,26,27] Scheme1.Transformation of carboxylic acids into hydroxamic acids: a) PyBOP,D IPEA, NH 2 OTHP,inTHF,RT4-24 h; b) HCl, in MeOH 20-70 8C, 6-24 h.…”

“…Sm HDAC8 can therefore be assumed to have specific and vital functions in schistosomes, and this was confirmed by transcript knockdown using RNAi that led to a significant decrease in worm development and survival in infected mice, cementing its status as a valuable potential target. So far, only a few series of Sm HDAC8 inhibitors have been reported, and most were only moderately effective against the parasite or showed no effect (Figure ). Based on virtual screening and structure‐guided optimization of a co‐crystallized hit ( J1038 , Figure ), we recently described a benzamidohydroxamic acid TH65 (Figure ) as an Sm HDAC8 inhibitor that is able to kill S. mansoni larvae in culture …”

Chemotherapy for Fighting Schistosomiasis: Past, Present and Future

“…Although the most potent compounds ( 27 and 28 , Figure B) showed good activity and selectivity profiles, the IC 50 values were higher than that of 24 . Furthermore, both compounds had a reduced lethal effect on the schistosomula in comparison to 24 …”

“… A) Development of 3‐amino‐ and 3‐amidobenzohydroxamates as antischistosomal agents and derivatives ( 25 and 26 ) of 24 (n.d.=not determined) . B) Chemical structures of isophthalic acid derivatives 27 and 28 . C) Chemical structures of the most potent BACADs .…”

“…[115,116] B) Chemical structures of isophthalic acid derivatives 27 and 28. [117] C) Chemical structures of the most potent BACADs. [123] D) Chemical structures of AASs 33-35 with antischistosomal activity.…”