A series of isoquinoline-1,3,4-trione derivatives were identified as novel and potent inhibitors of caspase-3 through structural modification of the original compound from high-throughput screening. Various analogues (2, 6, 9, 13, and 14) were synthesized and identified as caspase inhibitors, and the introduction of a 6-N-acyl group (compound 13) greatly improved their activity. Some of them showed low nanomolar potency against caspase-3 in vitro (for example, for 6k, IC50 = 40 nM) and significant protection against apoptosis in a model cell system. Additionally, compound 13f demonstrated a dose-dependent decrease in infarct volume in the transient MCA occlusion stroke model. The present small-molecule caspase-3 inhibitor with novel structures different from structures of known caspase inhibitors revealed a new direction for therapeutic strategies directed against diseases involving abnormally up-regulated apoptosis.

We analyzed the seroprevalence of tick-borne severe fever with thrombocytopenia syndrome virus (SFTSV) in farm-raised minks using double antigen ELISA (enzyme-linked immunosorbent assay) kit and indicated that 8.4% (15/178) of the minks had antibodies to the nucleoprotein of SFTSV and 72.7% (8/11) of mink farms had minks positive to SFTSV. The ELISA results were further confirmed by presence of neutralization to SFTSV in the mink sera. Our results suggested that minks were widely infected with SFTSV in China.