Benzofuran-chalcone hybrids as potential multifunctional agents against Alzheimer's disease: synthesis and in vivo studies with transgenic Caenorhabditis elegans.

Abstract

In the search for effective multifunctional agents for the treatment of Alzheimer's disease (AD), a series of novel hybrids incorporating benzofuran and chalcone fragments were designed and synthesized. These hybrids were screened by using a transgenic Caenorhabditis elegans model that expresses the human β-amyloid (Aβ) peptide. Among the hybrids investigated, (E)-3-(7-methyl-2-(4-methylbenzoyl)benzofuran-5-yl)-1-phenylprop-2-en-1-one (4 f), (E)-3-(2-benzoyl-7-methylbenzofuran-5-yl)-1-phenylprop-2-en-1-one (4 i), and (E)-3-(2-benzoyl-7-methylbenzofuran-5-yl)-1-(thiophen-2-yl)prop-2-en-1-one (4 m) significantly decreased Aβ aggregation and increased acetylcholine (ACh) levels along with the overall availability of ACh at the synaptic junction. These compounds were also found to decrease acetylcholinesterase (AChE) levels, reduce oxidative stress in the worms, lower lipid content, and to provide protection against chemically induced cholinergic neurodegeneration. Overall, the multifunctional effects of these hybrids qualify them as potential drug leads for further development in AD therapy.

• Authors: Koneni V Sashidhara, Ram K Modukuri, Pooja Jadiya, Ranga Prasad Dodda, Manoj Kumar, Balasubramaniam Sridhar, Vikash Kumar, Rizwanul Haque, Mohammad Imran Siddiqi, Aamir Nazir
• Journal: ChemMedChem (ChemMedChem) Vol. 9 Issue 12 Pg. 2671-84 (Dec 2014) ISSN: 1860-7187 [Electronic] Germany
• PMID: 25251917 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• 3-(2-benzoyl-7-methylbenzofuran-5-yl)-1-(thiophen-2-yl)prop-2-en-1-one
• 3-(2-benzoyl-7-methylbenzofuran-5-yl)-1-phenylprop-2-en-1-one
• 3-(7-methyl-2-(4-methylbenzoyl)benzofuran-5-yl)-1-phenylprop-2-en-1-one
• Amyloid beta-Peptides
• Antioxidants
• Benzofurans
• Chalcones
• Thiophenes
• Chalcone
• Acetylcholinesterase
• benzofuran
• Acetylcholine

Topics

• Acetylcholine (metabolism)
• Acetylcholinesterase (metabolism)
• Alzheimer Disease (drug therapy)
• Amyloid beta-Peptides (antagonists & inhibitors, genetics, metabolism)
• Animals
• Animals, Genetically Modified (metabolism)
• Antioxidants (chemical synthesis, pharmacology, therapeutic use)
• Benzofurans (chemistry, pharmacology, therapeutic use)
• Binding Sites
• Caenorhabditis elegans (metabolism)
• Chalcone (chemistry)
• Chalcones (chemistry, pharmacology, therapeutic use)
• Crystallography, X-Ray
• Disease Models, Animal
• Humans
• Microscopy, Fluorescence
• Molecular Conformation
• Molecular Docking Simulation
• Oxidative Stress (drug effects)
• Protein Structure, Tertiary
• Structure-Activity Relationship
• Thiophenes (chemistry, pharmacology, therapeutic use)