Design, synthesis, and biological evaluation of 4-(1H-1,2,3-triazol-1-yl)benzamides as HSP90 inhibitors

Heat shock protein 90 (HSP90) is a promising anticancer drug target, which could be employed to construct HSP90 inhibitors-based drug conjugates for selective tumor therapy. Herein, a series of 4-(1H-1,2,3-triazol-1-yl)benzamides were rationally designed, synthesized as HSP90 inhibitors, and their structures were characterized by H-1 NMR, C-13 NMR, and HR-MS. Preliminary HSP90 binding assay showed that compounds 6b, 61, 6m, 6n, 6t, and 6u exhibited significant HSP90 alpha binding affinity. Among these selected compounds, 6u displayed the most potent anti-proliferative activities and particularly in Capan-1 cell line. Molecular modeling studies also confirmed possible mode of interaction between 6u and the binding sites of HSP90 by hydrogen bond and hydrophobic interactions. Above all, these encouraging data indicated that 6u could be used as a HSP90 inhibitor for further study and helped the recognition of the 4-(1H-1,2,3-triazol-1-yl)benzamide motif as a new scaffold for HSP90 inhibitors. [GRAPHICS] .

Automated summary

Heat shock protein 90 (HSP90) is a promising target for anticancer drugs. In this study, a series of novel HSP90 inhibitors was synthesized and compound 6u exhibited the most potent anti-proliferative activity, particularly in Capan-1 cell line. Molecular modeling studies also confirmed the interaction mechanism between 6u and HSP90, suggesting it as a potential candidate for further research.