Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.
Mol Divers. 2019 Nov;23(4):897-913. doi: 10.1007/s11030-019-09917-8. Epub 2019 Jan 21.
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 values in the micromolar range. Compound 14b, 3-[(benzylamino)methylidene]-3,4-dihydro-2H-1-benzopyran-2,4-dione, was the most potent MAO-B inhibitor with an IC value of 638 µM. This compound was shown to be a reversible and competitive MAO-B inhibitor with a K 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.
基于报道称色酮化合物是单胺氧化酶（MAO）的有效抑制剂，本研究评估了在 3 位取代具有柔性侧链对 MAO 抑制活性的影响。通过在羰基二咪唑（CDI）存在下，用芳香族和脂肪族胺和醇与色酮 3-羧酸反应，合成了 15 种色酮衍生物。这得到了色烷-2,4-二酮和酯色酮衍生物。通常，酯类表现出较弱的 MAO 抑制活性，而色烷-2,4-二酮衍生物作为选择性 MAO-B 抑制剂具有希望，其 IC 值在微摩尔范围内。化合物 14b，3-[(苄氨基)亚甲基]-3,4-二氢-2H-1-苯并吡喃-2,4-二酮，是最有效的 MAO-B 抑制剂，IC 值为 638 µM。该化合物被证明是一种可逆和竞争性的 MAO-B 抑制剂，K 值为 94 µM。总之，探索了在色酮的 3 位延长链和引入柔性取代基的效果，结果表明亚氨基取代优于酯取代。具有良好活性的 MAO-B 抑制剂可能成为设计和开发治疗帕金森病的先导化合物，这些药物可减少多巴胺的中枢代谢。
