Issue 11, 2015

Tricyclic phenothiazine and phenoselenazine derivatives as potential multi-targeting agents to treat Alzheimer's disease

Abstract

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 μM; BuChE IC50 = 5.3 ± 0.5 μM), whereas in the corresponding phenoselenazine series, 13j (2-chloro-10H-phenoselenazin-10-yl-(4-methoxyphenyl)methanone) exhibited good non-selective cholinesterase inhibition (AChE IC50 = 5.8 ± 0.4 μM; BuChE IC50 = 4.9 ± 0.5 μM). Interestingly, N-10 unsubstituted phenothiazine 6a (AChE IC50 = 7.3 ± 0.6 μM; BuChE IC50 = 5.8 ± 0.5 μM; Aβ1–42 aggregation inhibition = 62%; DPPH scavenging = 92%), and the corresponding phenoselenazine bioisostere 12a (AChE IC50 = 5.6 ± 0.4 μM; BuChE IC50 = 3.0 ± 0.5 μM; Aβ1–42 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.

Graphical abstract: Tricyclic phenothiazine and phenoselenazine derivatives as potential multi-targeting agents to treat Alzheimer's disease

Article information

Article type
Concise Article
Submitted
28 Jun 2015
Accepted
30 Jul 2015
First published
07 Aug 2015

Med. Chem. Commun., 2015,6, 1930-1941

Tricyclic phenothiazine and phenoselenazine derivatives as potential multi-targeting agents to treat Alzheimer's disease

G. Tin, T. Mohamed, N. Gondora, M. A. Beazely and P. P. N. Rao, Med. Chem. Commun., 2015, 6, 1930 DOI: 10.1039/C5MD00274E

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