Design and Synthesis of Ranitidine Analogs as Multi-Target Directed Ligands for the Treatment of Alzheimer’s Disease |
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| Authors: | Jie Gao Chen Suo Jui-Heng Tseng Melissa A. Moss Alvin V. Terry Jr. James Chapman |
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| Affiliation: | 1.Department of Clinical and Diagnostic Science, University of Alabama at Birmingham, Birmingham, AL 35294, USA;2.Department of Chemical Engineering and Biomedical Engineering, University of South Carolina, Columbia, SC 29208, USA; (C.S.); (J.-H.T.); (M.A.M.);3.Department of Pharmacology and Toxicology, Augusta University, Augusta, GA 30912, USA;4.Department of Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA; |
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| Abstract: | The aggregation of amyloid β (Aβ) peptides and deposition of amyloid plaques are implicated in the pathogenesis of Alzheimer’s disease (AD). Therefore, blocking Aβ aggregation with small molecules has been proposed as one therapeutic approach for AD. In the present study, a series of ranitidine analogs containing cyclic imide isosteres were synthesized and their inhibitory activities toward Aβ aggregation were evaluated using in vitro thioflavin T assays. The structure–activity relationship revealed that the 1,8-naphthalimide moiety provided profound inhibition of Aβ aggregation and structural modifications on the other parts of the parent molecule (compound 6) maintained similar efficacy. Some of these ranitidine analogs also possessed potent inhibitory activities of acetylcholinesterase (AChE), which is another therapeutic target in AD. These ranitidine analogs, by addressing both Aβ aggregation and AChE, offer insight into the key chemical features of a new type of multi-target directed ligands for the pharmaceutical treatment of AD. |
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| Keywords: | Alzheimer’ s disease, amyloid β (Aβ ) aggregation, acetylcholinesterase, multi-target directed ligands, naphthalimide, thioflavin T |
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