期刊
MEDCHEMCOMM
卷 6, 期 11, 页码 1930-1941出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c5md00274e
关键词
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资金
- Ontario Mental Health Foundation
- NSERC-Discovery Grants [RGPIN 03830-2014, RGPIN 3713842013]
- Canada Foundation for Innovation (CFI-JELF) Leaders Fund
- Ministry of Research and Innovation, Government of Ontario, Canada for an Early Researcher Award
A group of tricyclic phenothiazines (6a, 6b and 7a-l) and phenoselenazines (12a, 12b and 13a-l) was designed, synthesized and evaluated as multi-targeting ligands aimed at the cholinergic, amyloid and oxidative stress pathways of Alzheimer's disease. The phenothiazine derivative 7j (2-chloro-10H-phenothiazin-10-yl-(4-methoxyphenyl)methanone) was identified as the best dual, non-selective cholinesterase inhibitor (AChE IC50 = 5.9 +/- 0.6 mu M; BuChE IC50 = 5.3 +/- 0.5 mu M), whereas in the corresponding phenoselenazine series, 13j (2-chloro-10H-phenoselenazin-10-yl-(4-methoxyphenyl)methanone) exhibited good nonselective cholinesterase inhibition (AChE IC50 = 5.8 +/- 0.4 mu M; BuChE IC50 = 4.9 +/- 0.5 mu M). Interestingly, N-10 unsubstituted phenothiazine 6a (AChE IC50 = 7.3 +/- 0.6 mu M; BuChE IC50 = 5.8 +/- 0.5 mu M; A beta(1-42) aggregation inhibition = 62%; DPPH scavenging = 92%), and the corresponding phenoselenazine bioisostere 12a (AChE IC50 = 5.6 +/- 0.4 mu M; BuChE IC50 = 3.0 +/- 0.5 mu M; A beta(1-42) aggregation inhibition = 45.6%; DPPH scavenging = 84.4%) were able to exhibit multi-targeting ability by demonstrating cholinesterase inhibition, beta-amyloid aggregation and antioxidant properties. These results show that fused tricyclic ring systems based on either phenothiazine or phenoselenazine templates can be useful to develop hybrid small molecules to target multiple pathological routes associated with Alzheimer's disease.
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