Electrophilic Warhead-Based Design of Compounds Preventing NLRP3 Inflammasome-Dependent Pyroptosis

Pyroptosis is a caspase-1-dependent
pro-inflammatory form of programmed
cell death implicated in the pathogenesis of autoinflammatory diseases
as well as in disorders characterized by excessive cell death and
inflammation. Activation of NLRP3 inflammasome is a key event in the
pyroptotic cascade. In this study, we describe the synthesis and chemical
tuning of α,β-unsaturated electrophilic warheads toward
the development of antipyroptotic compounds. Their pharmacological
evaluation and structure–activity relationships are also described.
Compound 9 was selected as a model of this series, and
it proved to be a reactive Michael acceptor, irreversibly trapping
thiol nucleophiles, which prevented both ATP- and nigericin-triggered
pyroptosis of human THP-1 cells in a time- and concentration-dependent
manner. Moreover, 9 and other structurally related compounds,
inhibited caspase-1 and NLRP3 ATPase activities. Our findings can
contribute to the development of covalent, multitarget antipyroptotic
compounds targeting molecular components of the NLRP3 inflammasome
regulatory pathway.