Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 20, Pages -Publisher
MDPI
DOI: 10.3390/ijms222011084
Keywords
JNK3; benzimidazole; neurodegenerative diseases; SAR; neuroprotection; Alzheimer's disease (AD)
Funding
- National Research Foundation of Korea [NRF-2019M3A9A8066500, NRF-2020R1A6A1A03042854, NRF-2021R1A2C2007159]
- Institute of Information and Communications Technology Planning and Evaluation (IITP) - Korean government (MSIT) [2020-0-01343]
- National Research Foundation of Korea [2019M3A9A8066500] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Ask authors/readers for more resources
In this study, a series of JNK3 inhibitors were synthesized and one compound exhibited excellent performance in terms of JNK3 inhibition and neuroprotective effects.
As members of the MAPK family, c-Jun-N-terminal kinases (JNKs) regulate the biological processes of apoptosis. In particular, the isoform JNK3 is expressed explicitly in the brain at high levels and is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this study, we prepared a series of five 6-dihydroxy-1H-benzo[d]imidazoles as JNK3 inhibitors and found them have potential as neuroprotective agents. Following a previous lead scaffold, benzimidazole moiety was modified with various aryl groups and hydroxylation, and the resulting compounds exhibited JNK3 inhibitory activity with improved potency and selectivity. Out of 37 analogues synthesized, (S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin -6-yl)-5,6-dihydroxy-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino) piperidin-1-yl)methanone (35b) demonstrated the highest JNK3 inhibition (IC50 = 9.7 nM), as well as neuroprotective effects against A beta-induced neuronal cell death. As a protein kinase inhibitor, it also showed excellent selectivity over other protein kinases including isoforms JNK1 (> 1000 fold) and JNK2 (-10 fold).
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available