Design, synthesis, and structure-activity relationship studies of 6H-benzo[b]indeno[1,2-d]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors.

ABSTRACT: A series of sulfur-containing tetracycles was designed and evaluated for their ability to inhibit protein kinase DYRK1A, a target known to have several potential therapeutic applications including cancers, Down syndrome or Alzheimer's disease. Our medicinal chemistry strategy relied on the design of new compounds using ring contraction/isosteric replacement and constrained analogy of known DYRK1A inhibitors, thus resulting in their DYRK1A inhibitory activity enhancement. Whereas a good inhibitory effect of targeted DYRK1A protein was observed for 5-hydroxy compounds 4i-k (IC₅₀ = 35-116 nM) and the 5-methoxy derivative 4e (IC₅₀ = 52 nM), a fairly good selectivity towards its known DYRK1B off-target was observed for 4k. In addition, the most active compound 4k, having a

SUBMITTER: Faouzi A 

PROVIDER: S-EPMC11487425 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature