Design, synthesis and biological evaluation of novel osthole-based derivatives as potential neuroprotective agents

Li Zhang; Yuhang Wu; Guixiang Yang; Haixian Gan; Dayong Sang; Jiye Zhou; Lin Su; Rui Wang; Lei Ma

doi:10.1016/j.bmcl.2020.127633

Design, synthesis and biological evaluation of novel osthole-based derivatives as potential neuroprotective agents

Bioorg Med Chem Lett. 2020 Dec 15;30(24):127633. doi: 10.1016/j.bmcl.2020.127633. Epub 2020 Oct 24.

Authors

Li Zhang¹, Yuhang Wu¹, Guixiang Yang¹, Haixian Gan¹, Dayong Sang², Jiye Zhou¹, Lin Su¹, Rui Wang³, Lei Ma⁴

Affiliations

¹ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
² College of Chemical Engineering and Pharmacy, Jingchu University of Technology, Jingmen, Hubei 448000, China.
³ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. Electronic address: ruiwang@ecust.edu.cn.
⁴ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. Electronic address: malei@ecust.edu.cn.

PMID: 33132198
DOI: 10.1016/j.bmcl.2020.127633

Abstract

A total of 26 compounds based on osthole skeleton were designed, synthesized. Their cytoprotective abilities of antioxidation, anti-inflammation and Aβ₄₂(Amyloid β-protein 42)-induced neurotoxicity were evaluated by MTT assays. Mechanism of the action of selected compounds were investigated by molecular docking. AlogP, logS and blood-brain barrier (BBB) permeability of all these compounds were simulated by admetSAR. Most of the compounds showed better antioxidative and anti-inflammatory activities compared with osthole, especially OST7 and OST17. The compound OST7 showed relative high activity in neuroprotection against H₂O₂ (45.7 ± 5.5%), oxygen glucose deprivation (64.6 ± 4.8%) and Aβ₄₂ (61.4 ± 5.2%) at a low concentration of 10 μM. EC₅₀ of selected compounds were measured in both H₂O₂ and OGD induced cytotoxicity models. Moreover, NO inhibiting ability of OST17(50.4 ± 7.1%) already surpassed the positive drug indomethacin. The structure activity relationship study indicated that introduction of piperazine group, tetrahydropyrrole group and aromatic amine group might be beneficial for enhancement of osthole neuroprotective properties. Molecular docking explained that the reason OST7 exhibited relatively stronger neuroprotection against Aβ because of the greater area of interactions between molecule and target protein. OST7 and OST17 both provided novel methods to investigate osthole as anti-AD drugs.

Keywords: Amyloid β-protein; Anti-inflammation; Antioxidant; Molecular docking; Neuroprotection; Osthole.

Publication types

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

MeSH terms

Alzheimer Disease / drug therapy
Alzheimer Disease / metabolism
Amyloid beta-Peptides / antagonists & inhibitors
Amyloid beta-Peptides / metabolism*
Coumarins / chemistry*
Coumarins / pharmacology*
Drug Design*
Humans
Molecular Docking Simulation
Neuroprotective Agents / chemistry*
Neuroprotective Agents / pharmacology*
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / metabolism*
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Coumarins
Neuroprotective Agents
Peptide Fragments
amyloid beta-protein (1-42)
osthol