2-(3-Hydroxybenzyl)benzo[d]isothiazol-3(2H)-one Mannich base derivatives as potential multifunctional anti-Alzheimer’s agents

A series of 2-(3-hydroxybenzyl)benzo[ d ]isothiazol-3(2 H )-one Mannich base derivatives were designed as potential multifunctional agents against Alzheimer’s disease. The twelve derivatives were synthesized and evaluated with various biological activities. In vitro, biological assays showed that most of the target compounds are selective AChE inhibitors and good antioxidants. Among them, compounds 6d and 13d are representative agents exhibiting significant selective AChE inhibition (IC 50 = 1.09 µM and 2.01 µM, respectively), potent antioxidant activity, moderate inhibition of self-induced A β 1–42 aggregation, selective metal-chelating activity with Fe 2+ and Cu 2+ , excellent neuroprotective effect on H 2 O 2 -induced PC12 cell injury and good BBB permeability. Moreover, the step-down passive avoidance test demonstrated that 6d and 13d can improve the scopolamine-induced cognitive deficit in mice. The above results suggested that compounds 6d and 13d can be envisioned as multifunctional lead compounds for further development of drugs against AD.