Novel 1-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-indene-4-thiol derivatives as potent selective human monoamine oxidase B inhibitors: Design, SAR development, and biological evaluation

Haiyan Kong; Xianshe Meng; Rui Hou; Xiaoxiao Yang; Jihong Han; Zhouling Xie; Yajun Duan; Chenzhong Liao

doi:10.1016/j.bmcl.2021.128051

Novel 1-(prop-2-yn-1-ylamino)-2,3-dihydro-1H-indene-4-thiol derivatives as potent selective human monoamine oxidase B inhibitors: Design, SAR development, and biological evaluation

Bioorg Med Chem Lett. 2021 Jul 1:43:128051. doi: 10.1016/j.bmcl.2021.128051. Epub 2021 Apr 19.

Authors

Haiyan Kong¹, Xianshe Meng¹, Rui Hou¹, Xiaoxiao Yang¹, Jihong Han¹, Zhouling Xie¹, Yajun Duan², Chenzhong Liao³

Affiliations

¹ Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China.
² Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China. Electronic address: yduan@hfut.edu.cn.
³ Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China. Electronic address: czliao@hfut.edu.cn.

PMID: 33887441
DOI: 10.1016/j.bmcl.2021.128051

Abstract

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.

Keywords: Fragment-based drug design; HMAO-B; Isoform selectivity; Structure activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Drug Design*
Humans
Indenes / chemical synthesis
Indenes / chemistry
Indenes / pharmacology*
Models, Molecular
Molecular Structure
Monoamine Oxidase / metabolism*
Monoamine Oxidase Inhibitors / chemical synthesis
Monoamine Oxidase Inhibitors / chemistry
Monoamine Oxidase Inhibitors / pharmacology*
Structure-Activity Relationship
Sulfhydryl Compounds / chemical synthesis
Sulfhydryl Compounds / chemistry
Sulfhydryl Compounds / pharmacology*

Substances

Indenes
Monoamine Oxidase Inhibitors
Sulfhydryl Compounds
indene
Monoamine Oxidase