Development of potent BChE/Nrf2 modulators for Alzheimer's disease treatment via dual suppression of ferroptosis.

Targeting multiple pathological mechanisms holds significant potential for Alzheimer's disease (AD) therapy. Here, we designed 50 hybrids combining the benzimidazole-aminofurazan scaffold of a BChE inhibitor (S06-1064) with the 1,2,4-oxadiazole moiety of an Nrf2 activator (6). After four optimization rounds, S27-1046 and S27-1047 emerged as potent, selective BChE inhibitors and Nrf2 activators (S27-1046: eqBChE IC50 = 2.51 ± 1.51 nM, hBChE IC50 = 128.30 ± 16.89 nM, FP IC50 = 188.20 ± 57.11 nM, 4.73-fold ARE induced fold at 20 μM; S27-1047: eqBChE IC50 = 7.16 ± 2.96 nM, hBChE IC50 = 296.10 ± 55.78 nM, FP IC50 = 36.87 ± 23.07 nM, 7.42-fold ARE induced fold at 20 μM). They directly bind Keap1, disrupt Keap1-Nrf2 interaction, enhance antioxidant enzyme expression, and activate the GSH-GPX4 axis to inhibit Aβ-induced ferroptosis. Both compounds also protect against oxidative stress and neuroinflammation. S27-1047 showed superior Nrf2 activation and Keap1 binding, thus was selected for in vivo evaluation. In an Aβ-induced AD mouse model, S27-1047 significantly improved cognition, outperforming mono- or combination therapies. It has 12.62% oral bioavailability and crosses the BBB. This work presents multi-target agents targeting BChE, Nrf2, and ferroptosis for effective AD therapy.