88628-47-1Relevant articles and documents
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.
α-Tetralone derivatives as inhibitors of monoamine oxidase
Legoabe, Lesetja J.,Petzer, Anél,Petzer, Jacobus P.
, p. 2758 - 2763 (2015/02/19)
In the present study, a series of fifteen α-tetralone (3,4-dihydro-2H-naphthalen-1-one) derivatives were synthesised and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The α-tetralone derivatives examined are structurally related to a series of chromone (1-benzopyran-4-one) derivatives which has previously been shown to act as MAO-B inhibitors. The results document that the α-tetralones are highly potent MAO-B inhibitors with all compounds exhibiting IC50 values in the nanomolar range (50 values in the nanomolar range (50 value of 4.5 nM with a 287-fold selectivity for MAO-B over the MAO-A isoform, while the most potent MAO-A inhibitor, 6-(3-cyanobenzyloxy)-3,4-dihydro-2H-naphthalen-1-one, exhibits an IC50 value of 24 nM with a 3.25-fold selectivity for MAO-A. Analyses of the structure-activity relationships for MAO inhibition show that substitution on the C6 position of the α-tetralone moiety is a requirement for MAO-A and MAO-B inhibition, and that a benzyloxy substituent on this position is more favourable for MAO-A inhibition than phenylethoxy and phenylpropoxy substitution. For MAO-B inhibition, alkyl and halogen substituents on the meta and para positions of the benzyloxy ring enhance inhibitory potency. It may be concluded that α-tetralone derivatives are promising leads for design of therapies for Parkinson's disease and depression.
