Design, synthesis, and biological evaluation of (E)-N′-substitute-4-((4-pyridylpyrimidin-2-yl)amino)benzohydrazide derivatives as novel potential CDK9 inhibitors

CDK9 is a promising drug target for treating many diseases such as cancer and HIV. In our previous studies, two series of 5-(substituted amino)-1H-indole-2-carbohydrazide derivatives were discovered as CDK9 inhibitors exhibiting potent HIV-1 transcription inhibition and anticancer activities. In a continuing effort to develop new CDK9 inhibitors endowed with good anticancer activity, we designed and synthesized a series of new benzene carbohydrazide derivatives bearing a (pyridyl pyrimidin-2-yl)amino moiety in position-4 of the phenyl ring. This work reports the preparation of benzene carbohydrazide derivatives, their inhibition effect on HIV-1 transcription, and the preliminary structure–activity relationships. Compound 9h was found to be the most potent CDK9 inhibitor and exhibited excellent anti-proliferative activities against cancer cells (A375, A549, HepG2, and MCF-7) but was less toxic to normal cells (MCF-10A and HaCaT). Further bioassays indicated that compound 9h could induce the apoptosis of cancer cells, which contributes to its antitumor effects. Finally, we performed molecular docking studies to predict the binding mode of 9h at the ATP binding site of CDK9 and identify the essential amino acids responsible for the interactions.