Synthesis and evaluation of chromone derivatives as inhibitors of monoamine oxidase

• Published in: Molecular diversity Vol. 23; no. 4; pp. 897 - 913
• Main Authors: Mpitimpiti, Annah N., Petzer, Jacobus P., Petzer, Anél, Jordaan, Johannes H. L., Lourens, Anna C. U.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-11-2019; Springer Nature B.V
• Subjects: Amines; Biochemistry; Biomedical and Life Sciences; Carboxylic acids; Chromones - chemical synthesis; Chromones - chemistry; Esters; Inhibition; Inhibitors; Life Sciences; Metabolism; Monoamine Oxidase - chemistry; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine Oxidase Inhibitors - chemistry; Organic Chemistry; Original Article; Parkinson's disease; Pharmacy; Polymer Sciences; Recombinant Proteins - chemistry; Competitive; Chromandione; Monoamine oxidase; Chromone; MAO; Inhibitor; Parkinson’s disease
• ISSN: 1381-1991; 1573-501X
• DOI: 10.1007/s11030-019-09917-8

Based on reports that chromone compounds are good potency inhibitors of monoamine oxidase (MAO), the present study evaluates the effect of substitution with flexible side chains on the 3 position on MAO inhibition potency. Fifteen chromone derivatives were synthesised by reacting aromatic and aliphatic amines and alcohols with chromone 3-carboxylic acid in the presence of carbonyldiimidazole (CDI). This yielded chromane-2,4-dione and ester chromone derivatives. Generally, the esters exhibited weak MAO inhibition, while the chromane-2,4-dione derivatives showed promise as selective MAO-B inhibitors with IC
50
values in the micromolar range. Compound
14b
, 3-[(benzylamino)methylidene]-3,4-dihydro-2
H
-1-benzopyran-2,4-dione, was the most potent MAO-B inhibitor with an IC
50
value of 638 µM. This compound was shown to be a reversible and competitive MAO-B inhibitor with a
K
i
of 94 µM. In conclusion, the effect of chain elongation and introduction of flexible substituents on position 3 of chromone were explored and the results showed that aminomethylidene substitution is preferable over ester substitution. Good potency MAO-B inhibitors may act as leads for the design and development of therapy for Parkinson’s disease where these agents reduce the central metabolism of dopamine.
Graphical abstract