Design, synthesis, and molecular docking studies of novel pyrazolyl 2-aminopyrimidine derivatives as HSP90 inhibitors

A series of novel pyrazolyl 2-aminopyrimidine derivatives (7a-t) were designed based on scaffold hopping techniques, synthesized and biologically evaluated for their HSP90 inhibition and anticancer activity. Several compounds exhibited potent HSP90 inhibition with IC₅₀ values less than that of the reference standard 17-AAG (1.25 µM). The most potent compound 7t displayed excellent HSP90 inhibition with an IC₅₀ of 20 nM and in vitro antiproliferative potential against three cancer cell lines (IC₅₀  < 5 µM). 7t also induced dose dependent degradation of client proteins (pHER2 and pERK1/2) in Western blot analysis. Several structural features of 7p-t oriented the molecules to retain all the essential binding interactions with HSP90, as observed by rationalized docking studies. Therefore, the para-nitrophenyl ring on the central pyrazole ring along with the 2-amino group on the pyrimidine ring are the crucial features in the development of novel HSP90 inhibitors based on this scaffold for targeted anticancer therapy.