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
Autor: | Chenzhong Liao, Zhouling Xie, Yajun Duan, Jihong Han, Rui Hou, Xianshe Meng, Haiyan Kong, Xiaoxiao Yang |
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Rok vydání: | 2021 |
Předmět: |
Models
Molecular Drug Monoamine Oxidase Inhibitors media_common.quotation_subject Clinical Biochemistry Pharmaceutical Science Pharmacology 01 natural sciences Biochemistry Neuroprotection Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Humans Structure–activity relationship Sulfhydryl Compounds Monoamine Oxidase Molecular Biology media_common Safinamide Rasagiline Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Nervous tissue Organic Chemistry In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry medicine.anatomical_structure Indenes Drug Design Molecular Medicine Monoamine oxidase B |
Zdroj: | Bioorganic & Medicinal Chemistry Letters. 43:128051 |
ISSN: | 0960-894X |
Popis: | 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. |
Databáze: | OpenAIRE |
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