Design,Synthesis And Biological Evaluation Of Novel Acridone Derivatives As ASK1 Inhibitors

Apoptosis signal-regulating kinase 1 (ASK1) has a broad range of biological functions depending on cellular context. A series of studies have revealed that ASK1 plays vital roles in many stress-related diseases, including cancer, cardiovascular and neurodegenerative diseases, suggesting it could serve as a potential therapeutic target. Thus, the development of potent ASK1 inhibitors would be beneficial to these diseases.Based on the previous analysis of ASK1 crystal structure, we established a structure based virtual screening mode to search ASK1 inhibtors with novel scaffolds. After two rounds of virtual screening via Discovery Studio (version 2.5), ten compounds were picked out from our own chemical library and SPECS commercial database. The in vitro ASK1 inhibitory activities of them were tested and 1H-pyrrolo [3,2-b] quinolin-9(4H)-one derivative 1-30 exhibited potent activity with ICso value of 1.05 μM.With 1-30 as lead compound,23 acridone derivatives were designed and synthesized as ASK1 inhibitors based on scraffold hopping and bioisosteric principle. The in vitro assay demonstrated that substitution in N10-substitution with suitable moiety is essential for ASK1 inhibition, and the basic moiety attached to acridone scraffold via a linkage also affects activity. Then, the modification on the compound N10-ethyl acridone A-13 was carried out through the change of substitutents on phenyl ring to explore the SAR. On the other hand, to investigate the influence of the length of carbon chains and the substitutent at the terminal on activity,15 acridone derivatives were synthesized based on the structure of compound A-23. A preliminary SAR was discussed for all the above target compoundsAccording to literature and the above resluts, a ring-breaking strategy was carried out and acridone scraffold was converted to quinolone ring, with the introduction of different heteromatic fragments into the amide group, five quinolone-3-carboxamide derivatives were synthesized as novel ASK1 inhibitors.