Synthesis and Evaluation of the 4-Substituted 2-Hydroxy-5-Iodochalcones and Their 7-Substituted 6-Iodoflavonol Derivatives for Inhibitory Effect on Cholinesterases and β-Secretase

• Main Authors: Malose J. Mphahlele, Emmanuel N. Agbo, Samantha Gildenhuys
• Format: Article
• Language: English
• Published: MDPI AG 2018-12-01
• Series: International Journal of Molecular Sciences
• Subjects: 4-substituted 2-hydroxy-5-iodochalcones; 7-substituted 6-iodoflavonols; X-ray; cholinesterases; BACE-1; molecular docking
• Online Access: https://www.mdpi.com/1422-0067/19/12/4112

A series of 2-aryl-3-hydroxy-6-iodo-4<i>H</i>-chromen-4-ones substituted at the 7-position with a halogen atom (<i>X</i> = F, Cl and Br) or methoxy group and their corresponding 4-substituted 2-hydroxy-5-iodochalcone precursors were evaluated in vitro for inhibitory effect against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and &#946;-secretase (BACE1) activities. Although moderate inhibitory effect was observed for the chalcones against AChE, derivatives <b>2h</b>, <b>2j</b> and <b>2n</b> exhibited significant inhibitory effect against BChE and BACE-1. The 2-aryl-7-fluoro-8-iodoflavonols <b>3b</b> and <b>3c</b>, on the other hand, exhibited increased activity and selectivity against AChE and reduced effect on BACE-1. The flavonols <b>3h</b>, <b>3i</b>, <b>3k</b>, <b>3l</b> and <b>3p</b> exhibited moderate inhibitory effect against AChE, but significant inhibition against BChE. Compounds <b>2j</b> and <b>3l</b> exhibited non-competitive mode of inhibition against BACE-1. Molecular docking predicted strong interactions with the protein residues in the active site of BACE-1 implying these compounds bind with the substrate. Similarly docking studies predicted interaction of the most active compounds with both CAS and PAS of either AChE or BChE with mixed type of enzyme inhibition confirmed by kinetic studies.