Novel RSK2Inhibitors Lead Compound Structural Optimization And SAR Studies

Using the ligand-based virtual screening program SHAFTS and structure-based virtual screening protocols, our group discovered variety of compounds with potent inhibitory activities against RSK2, through structural optimization, two series of compounds based on lead compound scaffolds were designed and synthesized. Its structure and activity relationship (SAR) was carried out by assay evaluation, some next structure optimization clues were obtained.The first series (A series) compounds was the derivatives of benzoyl hydrazine compounds. Through the introduction of an electron withdrawing group on the benzene ring or a pyridine ring, an electron donating group, and hydrogen bond donor, receptors, etc., the design and synthesis of the target compounds were synthesized, wherein the15compounds have not been reported. Such structural compound as RSK2small molecule kinase inhibitor were novel drug molecules. And biological test results confirmed the structural modification of the benzoyl moiety was effective, so we conducted a comprehensive studies of the meta-substituted. This suggested that the impossible for further structural transformation.Through the analysis of the biological test results on a series of compounds, the second series (B series) was designed and synthesized from the two higher inhibition ratio benzohydrazide5-(trifluoromethyl) pyridine compound as our derivative modified target. By introducing substituents in different sites and different lipophilic groups, to further improve the biological activity of this kind of compound. To achieve the structural modification of the fundamental basis by reserving hydrazide5-(trifluoromethyl) pyridine structure, a series of compounds (B) RSK2activity were synthesized, their activities are still ongoing and not yet modified the structure of discussions.