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. 2021 Feb;25(1):491-507. doi: 10.1007/s11030-020-10143-w. Epub 2020 Sep 24.
Monoamine oxidase (MAO) is of much clinical relevance, and inhibitors of this enzyme are used in the treatment for neuropsychiatric and neurodegenerative disorders such as depression and Parkinson's disease. The present study synthesises and evaluates the MAO inhibition properties of a series of 33 1-tetralone and 4-chromanone derivatives in an attempt to discover high-potency compounds and to expand on the structure-activity relationships of MAO inhibition by these classes. Among these series, eight submicromolar MAO-A inhibitors and 28 submicromolar MAO-B inhibitors are reported, with all compounds acting as specific inhibitors of the MAO-B isoform. The most potent inhibitor was a 1-tetralone derivative (1h) with IC values of 0.036 and 0.0011 µM for MAO-A and MAO-B, respectively. Interestingly, with the reduction of 1-tetralones to the corresponding alcohols, a decrease in MAO inhibition potency is observed. Among these 1-tetralol derivatives, 1p (IC = 0.785 μM) and 1o (IC = 0.0075 μM) were identified as particularly potent inhibitors of MAO-A and MAO-B, respectively. Potent compounds such as those reported here may act as leads for the future development of MAO-B specific inhibitors. The present study describes the MAO inhibitory activities of a series of 1-tetralone and 4-chromanone derivatives. Numerous high-potency MAO-B specific inhibitors were identified.
单胺氧化酶（MAO）具有重要的临床意义，其抑制剂被用于治疗神经精神和神经退行性疾病，如抑郁症和帕金森病。本研究合成并评估了一系列 33 个 1-四氢萘酮和 4-色满酮衍生物的 MAO 抑制特性，试图发现高活性化合物，并扩展这些化合物对 MAO 抑制的构效关系。在这些系列中，报告了 8 个亚毫摩尔 MAO-A 抑制剂和 28 个亚毫摩尔 MAO-B 抑制剂，所有化合物均作为 MAO-B 同工型的特异性抑制剂。最有效的抑制剂是 1-四氢萘酮衍生物（1h），对 MAO-A 和 MAO-B 的 IC 值分别为 0.036 和 0.0011 μM。有趣的是，随着 1-四氢萘酮还原为相应的醇，MAO 抑制活性降低。在这些 1-四氢醇衍生物中，1p（IC=0.785 μM）和 1o（IC=0.0075 μM）分别被鉴定为 MAO-A 和 MAO-B 的特别有效的抑制剂。像这里报道的那些有效化合物可以作为未来 MAO-B 特异性抑制剂的先导化合物。本研究描述了一系列 1-四氢萘酮和 4-色满酮衍生物的 MAO 抑制活性。鉴定出许多高活性的 MAO-B 特异性抑制剂。
