Synthesis And Evaluation Of 1,2-Benzisothiazol-3-One Derivatives As Caspase-3 Inhibitors

Apoptosis, or programmed cell death, is an essential physiological process of tissue development and homeostasis. The pathogenesis of many diseases is closely connected with aberrantly regulated apoptosis. Caspase family is involved in the whole process of apoptosis. Caspase-3 protease is apoptosis performer and plays a key role during the apoptotic process. A lot of functional disorded diseases that harm to human health are associated with the abnormal activation of caspase-3. Caspase-3 is considered as a valuable drug development target and the exploration of caspase-3 inhibitors become a research focus.Recently, 1,2-benzisothiazol-3-one was identified as lead compound of caspase-3 inhibitor by high throughput screening and a series of compounds containing urea structure had been synthesized. However, the poor solubility and cell penetration of urea derivatives was exposed on the cell experiments. Through structural modification we now plan to change the urea group to the amide group and synthesize a novel series of N-acyl-substituted 1,2-benzisothiazol-3-one amide derivatives to improve the water-solubility and permeability.In this paper,36 1,2-benzisothiazole-3-one amide derivatives, including 35 new unreported compounds were synthesized. The synthesized amide derivatives were examined for their ability to inhibit the activity of recombinant human effector caspase-3 and-7. Most compounds displayed IC50 values in the nM range against caspase-3 and-7. The inhibitory activity against caspase-3 was mainly related to the length of the carbon chain. Among the tested compounds, compound 24 and 25 exhibited the most potent caspase-3/-7 inhibitory activity with IC50= 34.9 nmol/L and 51.9 nmol/L, respectively. Additionally, the antiapoptotic activities of them were initially evaluated in human Jurkat T cells, as a cell-based model of apoptosis. They had a good cell protection from apoptosis. To clerity the potency of the synthesized compounds, compounds of the least activity 11 and the best activity 24 were docked into the active site of caspase-3. Through the binding model of synthesized inhibitors with caspase-3 active sites explained the reason for the level of activity. In summary, 1,2-benzisothiazole-3-one amide derivatives have more improved solubility and permeability, comparing to that of previously reported urea derivatives. That will be helpful to further animal test of those compounds.