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Bioorg Med Chem Lett. 2016 Nov 15;26(22):5573-5579. doi: 10.1016/j.bmcl.2016.09.072. Epub 2016 Oct 6.

Synthesis and biological evaluation of ranitidine analogs as multiple-target-directed cognitive enhancers for the treatment of Alzheimer's disease.

Author information

1
Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA; Department of Pharmacology and Toxicology, Augusta University, Health Sciences Campus, CB-3530, 1459 Laney Walker Blvd., Augusta, GA 30912, USA.
2
Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA.
3
Department of Pharmacology and Toxicology, Augusta University, Health Sciences Campus, CB-3530, 1459 Laney Walker Blvd., Augusta, GA 30912, USA.
4
Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA. Electronic address: mcinnes@sccp.sc.edu.

Abstract

Using molecular modeling and rationally designed structural modifications, the multi-target structure-activity relationship for a series of ranitidine analogs has been investigated. Incorporation of a variety of isosteric groups indicated that appropriate aromatic moieties provide optimal interactions with the hydrophobic and π-π interactions with the peripheral anionic site of the AChE active site. The SAR of a series of cyclic imides demonstrated that AChE inhibition is increased by additional aromatic rings, where 1,8-naphthalimide derivatives were the most potent analogs and other key determinants were revealed. In addition to improving AChE activity and chemical stability, structural modifications allowed determination of binding affinities and selectivities for M1-M4 receptors and butyrylcholinesterase (BuChE). These results as a whole indicate that the 4-nitropyridazine moiety of the JWS-USC-75IX parent ranitidine compound (JWS) can be replaced with other chemotypes while retaining effective AChE inhibition. These studies allowed investigation into multitargeted binding to key receptors and warrant further investigation into 1,8-naphthalimide ranitidine derivatives for the treatment of Alzheimer's disease.

KEYWORDS:

Acetylcholinesterase; Alzheimers Disease; Multi-target; Ranitidine

PMID:
27769620
PMCID:
PMC5185470
DOI:
10.1016/j.bmcl.2016.09.072
[Indexed for MEDLINE]
Free PMC Article

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