拉萨吉林
化学
单胺氧化酶
单胺氧化酶B
药理学
茚
神经保护
组合化学
立体化学
酶
生物化学
帕金森病
药物化学
疾病
医学
内科学
作者
Haiyan Kong,Xianshe Meng,Rui Hou,Xiaoxiao Yang,Jihong Han,Zhouling Xie,Yajun Duan,Chenzhong Liao
标识
DOI:10.1016/j.bmcl.2021.128051
摘要
Successes have been achieved in developing human monoamine oxidase B (hMAO-B) inhibitors as anti-Parkinson's disease (PD) drugs. However, low efficiency and unwanted side effects of the marketed hMAO-B inhibitors hamper their medical applications, therefore, novel potent selective hMAO-B inhibitors are still of great interest. 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 ROS formation and potential neuroprotective activity. Further mice behavioral tests demonstrated these two compounds have good therapeutic effects on 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.
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