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

Jie Gao, Narasimha Midde, Jun Zhu, Alvin V Terry, Campbell McInnes, James M. Chapman

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5573-5579
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number22
DOIs
StatePublished - Jan 1 2016

Fingerprint

Nootropic Agents
Ranitidine
Naphthalimides
Alzheimer Disease
Imides
Derivatives
Butyrylcholinesterase
Molecular modeling
Chemical stability
Hydrophobic and Hydrophilic Interactions
Catalytic Domain
Inhibition (Psychology)

Keywords

  • Acetylcholinesterase
  • Alzheimers Disease
  • Multi-target
  • Ranitidine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Synthesis and biological evaluation of ranitidine analogs as multiple-target-directed cognitive enhancers for the treatment of Alzheimer's disease. / Gao, Jie; Midde, Narasimha; Zhu, Jun; Terry, Alvin V; McInnes, Campbell; Chapman, James M.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 22, 01.01.2016, p. 5573-5579.

Research output: Contribution to journalArticle

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