Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases.
The development of remedies against the Alzheimer's disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30μM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE.
Bereich Organische Chemie, Martin-Luther-Universität Halle-Wittenberg, Institut für Chemie-Organische Chemie, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany.
Stefan
S
Schwarz
Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
Susana Dias
SD
Lucas
Bereich Organische Chemie, Martin-Luther-Universität Halle-Wittenberg, Institut für Chemie-Organische Chemie, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany.
Sven
S
Sommerwerk
Bereich Organische Chemie, Martin-Luther-Universität Halle-Wittenberg, Institut für Chemie-Organische Chemie, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany. Electronic address: rene.csuk@chemie.uni-halle.de.
René
R
Csuk
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002091:Butyrylcholinesterase / Q000097:blood / Q000378:metabolism*; D002175:Candida / Q000201:enzymology; D029441:Carica / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004524:Eels; D006034:Glycyrrhetinic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006736:Horses; D007700:Kinetics; D008049:Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D041681:NIH 3T3 Cells; D010206:Papain / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D008049:Lipase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D010206:Papain; D006034:Glycyrrhetinic Acid
Cholinesterase inhibitors; Docking studies; Ellman’s test; Glycyrrhetinic acid