Diarylthiophenes as inhibitors of the pore-forming protein perforin

https://doi.org/10.1016/j.bmcl.2015.12.003Get rights and content
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Abstract

Evolution from a furan-containing high-throughput screen (HTS) hit (1) resulted in isobenzofuran-1(3H)-one (2) as a potent inhibitor of the function of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 NK cells. In the current study, structure–activity relationship (SAR) development towards a novel series of diarylthiophene analogues has continued through the use of substituted-benzene and -pyridyl moieties as bioisosteres for 2-thioxoimidazolidin-4-one (A) on a thiophene (B) -isobenzofuranone (C) scaffold. The resulting compounds were tested for their ability to inhibit perforin lytic activity in vitro. Carboxamide (23) shows a 4-fold increase over (2) in lytic activity against isolated perforin and provides good rationale for continued development within this class.

Abbreviations

HTS
high-throughput screen
SAR
structure–activity relationships
PRF
perforin
CTL
cytotoxic T lymphocytes
NK
natural killer cells
PAINS
pan-assay interference compounds
AgNO3
silver(I) nitrate
KF
potassium fluoride
PFP
pentafluorophenyl
DCC
N,N′-dicyclohexylcarbodiimide
HOBt
hydroxybenzotriazole
EDCI
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
DMF
dimethylformamide
KOAc
potassium acetate
DMSO
dimethyl sulfoxide
THF
tetrahydrofuran

Keywords

Perforin
Perforin inhibitor
Diarylthiophene
Bioisostere
Immunosuppressant

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