1287312-28-0Relevant academic research and scientific papers
The evaluation of 1-tetralone and 4-chromanone derivatives as inhibitors of monoamine oxidase
Cloete, Stephanus J.,N’Da, Clarina I.,Legoabe, Lesetja J.,Petzer, Anél,Petzer, Jacobus P.
, p. 491 - 507 (2020/10/02)
Abstract: 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 IC50 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 (IC50 = 0.785?μM) and 1o (IC50 = 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. Graphic abstract: 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.[Figure not available: see fulltext.].
Neuroprotective effects of benzyloxy substituted small molecule monoamine oxidase B inhibitors in Parkinson's disease
Wang, Zhimin,Wu, Jiajia,Yang, Xuelian,Cai, Pei,Liu, Qiaohong,Wang, Kelvin D.G.,Kong, Lingyi,Wang, Xiaobing
, p. 5929 - 5940 (2016/11/09)
The benzyloxy substituted small molecules are well-known highly potent monoamine oxidase B inhibitors, but their therapeutic potential against Parkinson's disease have not been investigated in detail. In this paper, a series of representative benzyloxy substituted derivatives were synthesized and evaluated for MAO-A/B inhibition. In addition, their neuroprotective effects were investigated in 6-OHDA- and rotenone-treated PC12 cells. It was observed that most of the compounds exhibited a marked increase in survival of PC12 cells which treated with the neurotoxins. Among them, 13 exhibited remarkable and balanced neuroprotective potency. The protective effects of 13 against neurotoxins-induced apoptosis were confirmed with flow cytometry and staining methods. Furthermore, 13 also showed good BBB permeability and low toxicity according to in vitro BBB prediction and in vivo acute toxicity test. The results indicated that 13 is an effective and promising candidate to be further developed as disease-modifying drug for Parkinson's disease therapy.
Chromanones: selective and reversible monoamine oxidase B inhibitors with nanomolar potency
Lan, Jin-Shuai,Xie, Sai-Sai,Huang, Ming,Hu, Ya-Jian,Kong, Ling-Yi,Wang, Xiao-Bing
, p. 1293 - 1302 (2015/07/15)
A new series of C7-substituted chromanones has been designed, synthesized and evaluated for hMAO-B inhibitory activity in vitro. Most of the studied compounds were remarkably potent and selective MAO-B inhibitors and showed weak or no inhibition of MAO-A. Especially, compound 4f (IC50 = 8.62 nM) was the best MAO-B inhibitor and exhibited the highest selectivity for MAO-B (SI > 11 627.9-fold). In addition, the structure-activity relationships for MAO-B inhibition indicated that substitutions at the C7 of the chromanone moiety, particularly with the halogen substituted benzyloxy, were more favorable for MAO-B inhibition. Molecular docking studies have been performed to explore the interaction modes of C7-substituted chromanones with MAO-B. Furthermore, the representative compounds 4f and 5d showed low neurotoxicity in SH-SY5Y cells in vitro. So the C7-substituted chromanones could be used to develop promising drug candidates for the therapy of neurodegenerative diseases.
