Design Synthesis of Gardenamide A/Tacrine Hybrids and Their Protection against 6-Hydroxydopamine-Induced Insults in PC12 Cells

Abstract

Seven gardenamide A (GA)/tacrine hybrids have been designed and synthesized. Firstly, 10-gardenamide A (DG) aldehyde was prepared through 5 steps reactions applied genipin as starting material. The overyield was 20.4%. Then, N-terminated aminoalkyltacrine (TN-n) was synthesized via 4 steps reactions started from o-aminobenzoic acid. The overall yield was 50.0%～65.4%. After that, DG reacted with TN-n at the presence of appropriate reductant leading to the target compounds. The yields were from 37% to 54%. The structures of all the target compounds were confirmed by 1 H NMR, 13 C NMR and ESI-MS. The bioactivities of all the hybrids were evaluated by setting up 6-hydroxydopamine-induced impaired PC12 cell model. It was indicated that two hybrids TNG-1 and TNG-5 showed better neuroprotective activity than tacrine, GA or their combination. Based on this fact, it was proposed that the hybrids TNG-1 and TNG-5 were better drug-like candidates than both monomers. 有机化学 研究论文 874