Novel AP2238-clorgiline hybrids as multi-target agents for the treatment of Alzheimer?s disease: Design, synthesis, and biological evaluation

Cholinesterase and monoamine oxidase are potential targets for the therapy of Alzheimer's disease. A series of novel AP2238-clorgiline hybrids as multi-target agents were designed, synthesized and investigated in vitro for their inhibition of cholinesterases and monoamine oxidases. Many compounds displayed balanced and good inhibitory activity against AChE, BuChE and MAO-B with an obvious selective inhibitory effect on MAO-B. Among them, Compound 5l showed the most balanced potency to inhibit ChEs (eeAChE: IC50 = 4.03 +/- 0.03 mu M, eqBuChE: IC50 = 5.64 +/- 0.53 mu M; hAChE: IC50 = 8.30 +/- 0.04 mu M, hBuChE: IC50 = 1.91 +/- 0.06 mu M) and hMAO-B (IC50 = 3.29 +/- 0.09 mu M). Molecular modeling and kinetic studies showed that 5l was a mixed inhibitor for both AChE and BuChE, and a competitive MAO-B inhibitor. Compound 5l exhibited no toxicity to PC12 and BV-2 cells at 12.5 mu M and no acute toxicity at a dosage of 2500 mg/kg. Moreover, 5l can improve the memory function of mice with scopolamine-induced memory impairment and have an excellent ability to cross the blood-brain barrier. Overall, these findings suggested that compound 5l could be deemed as a promising, balanced multi-target drug candidate against Alzheimer's disease.