Synthesis of Benzoisoxazole Derivatives and Evaluation of Inhibitory Potency against Cholinesterase for Alzheimer's Disease Therapeutics

Research paper by Jung‐Youl Park, Sujeong Shin, Jae‐kwan Kim, kyoung Chan Park, Jeong Ho Park

Indexed on: 03 Sep '16Published on: 29 Aug '16Published in: Bulletin of the Korean Chemical Society


To improve Alzheimer's disease (AD) therapeutics, we have designed and synthesized new benzoisoxazole derivatives that are potent inhibitors of cholinesterase (acetylcholinesterase [AChE] and butyrylcholinesterase [BuChE]). Since inhibition of cholinesterase (ChE) is still considered to be one of the most effective ways of treating AD patients, many new classes of ChE inhibitors have been synthesized. To identify a new type of cholinergic drug, the benzoisoxazole moiety which is the pharmacophore moiety of Risperidone was coupled with natural antioxidants. Some benzoisoxazole derivatives (26–28 and 30) were found to effectively inhibit BuChE (IC50 < 20 μM), and some (20 and 26–28) to moderately inhibit AChE (IC50 < 100 μM). Furthermore, compound 28 showed better inhibitory activity against BuChE (IC50 = 0.72 ± 0.11 μM) than galantamine (IC50 = 8.4 ± 0.1 μM). The new benzoisoxazole derivatives showing BuChE inhibitory activity represent a new class of ChE inhibitor and can be used to create novel compound derivative drugs for treating AD patients.