| Parkinson’s disease(PD),a progressive neurodegenerative disease,poses serious health risks to middle-aged and older people and a heavy economic burden to society.It has been shown that human monoamine oxidase B(hMAO-B)is involved in the occurrence and development of PD,and inhibition of this enzyme can improve the symptoms of PD patients.Currently,marketed hMAO-B inhibitors include resagiline,selagiline,and safinamide,which boost dopamine levels and show a more favorable safety profile than other drugs in relieving PD symptoms.However,selectivity issues of these drugs have raised side effects such as liver toxicity and cheese effect,and hampered their further usage in medicine.Therefore,development of novel,highly potent and selective MAO-B inhibitors with low side effects is of great interests.Herein we report 1-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-indene-4-thiol derivatives as hMAO-B inhibitors,which were designed by employing a fragment-based drug design strategy to link rasagiline to hydrophobic fragments.Among the synthesized 31 compounds,K8 and K24 demonstrated very encouraging hMAO-B inhibitory activities and selectivity over hMAO-A,better than rasagiline and safinamide.In vitro studies indicated that K8 and K24 are nontoxic to nervous tissue cells and they have considerable effects against reactive oxygen specie(ROS)formation and potential neuroprotective activity.Further mice behavioral tests demonstrated these two compounds have good therapeutic effects on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced PD model mice.All these experiment results suggest that compounds K8 and K24 can be promising candidates for further research for treatment of PD. |
