A novel class of pyrazole analogues as aurora kinase A inhibitor: design, synthesis, and anticancer evaluation

Pyrazole, as a small molecule, was discovered for higher cytotoxicity and affinity towards Aurora-A kinase. Based on these facts, a novel pyrazole substituted at the 4^th position was designed, synthesized, and evaluated against MCF-7, MDA-MB-23, and Vero (non-cancerous kidney cell) cell lines. Compounds5hand5eexhibited greater cytotoxicity in the series against MCF-7 and MDA-MB-231, with GI₅₀ values of 0.12 µM and 0.63 µM, respectively, as compared to Imatinib (GI₅₀ values of 16.08 µM and 10.36 µM). All of the compounds displayed selective cytotoxicity against cancer cells but not on normal Vero cells, supporting the design strategy to be a selective anticancer agent. Furthermore, compounds 5h and 5e inhibited Aurora-A kinase with IC₅₀ values of 0.78 µM (4.70-fold) and 1.12 µM (2.84-fold), respectively, as compared to alisertib (IC₅₀ = 3.36 µM). In addition, compound 5h significantly arrested the cell cycle at G2/M (34.89 %, 5.56-fold) and the apoptotic phase (25.04 %, 11.81-fold) compared to the control. It also triggered an increase in early (7.43 %) and late (14.89 %) phase apoptosis compared to vehicle (0.235 and 0.36 %, respectively), causing 37.89-fold higher total apoptosis in the annexin-V assay. These data imply that Aurora-A kinase inhibition may be linked to apoptosis induction and cell cycle arrest. Furthermore, their higher docking score in the study confirmed evidence of Aurora-kinase suppression. It was observed that fluorine and imidazole increased the H-bond and lipophilic interactions with the binding residue. Also, the substitution of electron-rich and lipophilic groups increased hydrophobic interactions. Moreover, the three-atom linkage (CH₂NHCH₂) expanded compound 5h to fill the cavity. Based on current findings, it is concluded that compounds 5h and 5e with strong Aurora-A kinase suppression may be promising anticancer agents.