Development of Indole-3-yl-methylene-thiobarbital Derivatives as Inhibitors of HDAC8 Enzyme Activity

  • J Med Chem. 2026 Jul 23;69(14):16381-16400. doi: 10.1021/acs.jmedchem.5c03170.
Abdelrahman A F Elsayed  1  2 ,  Jianqiu Zhang  1 ,  Alvan F Shalas  1  3 ,  Petra E van der Wouden  1 ,  Donald J M van Pinxteren  4 ,  Willem Jespers  4 ,  Frank J Dekker  1
Affiliations
  • 1. Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Groningen 9713AV, The Netherlands.
  • 2. Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
  • 3. Department of Pharmacy, Faculty of Medicine, Brawijaya University, Jl. Veteran, Malang, East Java 65145, Indonesia.
  • 4. Medicinal Chemistry, Photopharmacology and Imaging, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Groningen 9713AV, The Netherlands.
PMID: 42406494 DOI: 10.1021/acs.jmedchem.5c03170
Abstract

Histone deacetylase 8 (HDAC8), a zinc-dependent class I enzyme, plays key roles in regulating gene expression and is implicated in various malignancies. Although hydroxamic acid-based inhibitors, like PCI-34051, have demonstrated potent HDAC8 inhibition, limitations including poor selectivity, instability, and off-target effects underscore the need for novel scaffolds. Here, we designed and synthesized a series of indole-based (thio)barbiturate derivatives to identify selective HDAC8 inhibitors. Compound 3d showed promising potency (IC50 = 2.9 μM) and selectivity for HDAC8 over Other isoforms. Structure-activity relationship studies revealed that thiobarbituric acid and 2-methylindole scaffolds enhanced HDAC8 inhibition. Remarkably, compound 3r emerged as the most potent inhibitor (IC50 = 0.08 μM), exhibiting slow-binding kinetics, nanomolar potency, and high selectivity over HDAC1, 2, 3, and 6. Furthermore, compound 3r selectively induced SMC3 hyperacetylation in THP-1 cells, confirming its functional HDAC8 inhibition. Computational modeling and molecular dynamics simulations rationalized the experimental SAR and suggested an allosteric mechanism of inhibition.

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