Structure-Activity Relationship Analysis of 3-Phenylcoumarin-Based Monoamine Oxidase B Inhibitors

Abstract

Monoamine oxidase B (MAO-B) catalyzes deamination of monoamines such as neurotransmitters dopamine and norepinephrine. Accordingly, small-molecule MAO-B inhibitors potentially alleviate the symptoms of dopamine-linked neuropathologies such as depression or Parkinson's disease. Coumarin with a functionalized 3-phenyl ring system is a promising scaffold for building potent MAO-B inhibitors. Here, a vast set of 3-phenylcoumarin derivatives was designed using virtual combinatorial chemistry or rationally de novo and synthesized using microwave chemistry. The derivatives inhibited the MAO-B at 100 nM−1 μM. The IC50 value of the most potent derivative 1 was 56 nM. A docking-based structure-activity relationship analysis summarizes the atom-level determinants of the MAO-B inhibition by the derivatives. Finally, the cross-reactivity of the derivatives was tested against monoamine oxidase A and a specific subset of enzymes linked to estradiol metabolism, known to have coumarin-based inhibitors. Overall, the results indicate that the 3-phenylcoumarins, especially derivative 1, present unique pharmacological features worth considering in future drug development.

Blocking oestradiol synthesis pathways with potent and selective coumarin derivatives

“…For that reason, the inhibition levels of the analogues were studied here against both enzyme subtypes ( Table 1 ). Analogous to earlier studies 18 , 49–51 analogues showing HSD1 inhibition also blocked the MAO-B activity at 10 µM. However, of the HSD1 inhibitor analogues presented in this study, only 6 ( Figure 6(A) ) and 7 have pIC 50 above 6 (IC 50 < 1 µM).…”

“…Monoamine oxidases (MAO) A and B are inhibited to some degree by the 3-phenylcoumarin analogues and this effect is notable for the MAO-B (see e.g. 18 , 48 , 49 ). For that reason, the inhibition levels of the analogues were studied here against both enzyme subtypes ( Table 1 ).…”

Inhibition of human CYP1 enzymes by a classical inhibitor α‐naphthoflavone and a novel inhibitor N‐(3, 5‐dichlorophenyl)cyclopropanecarboxamide: An in vitro and in silico study

“…Synthesis and experimental data for compounds 1 – 6 (3‐(4‐trifluoromethylphenyl)‐6‐methoxycoumarin ( 1 ), 3‐(4‐trifluoromethoxyphenyl)‐7‐methoxycoumarin ( 2 ), 3‐(3‐hydroxyphenyl)‐6‐hydroxycoumarin ( 3) , 3‐(3‐methoxyphenyl)‐7‐methoxycoumarin ( 4) , 3‐(3‐methoxyphenyl)‐6‐methoxycoumarin ( 5) , 3‐(3‐benzyloxyphenyl)‐7‐methoxycoumarin ( 6 ; Figure 1b) have been published earlier (Juvonen, Ahinko, Huuskonen, Raunio, & Pentikainen, 2019; Niinivehmas et al, 2018; Rauhamäki et al, 2018).…”

2‐Phenyloxazole‐4‐carboxamide as a Scaffold for Selective Inhibition of Human Monoamine Oxidase B

“…Various generations of MAO inhibitors have been developed with the aim of decreasing their adverse side effects such as hypertensive crisis, liver toxicity, and sleep disturbance and headache, as observed with some MAO‐A inhibitors. Starting more than 50 years ago with hydrazine derivatives (e.g., iproniazide) and then propargylamine derivatives (clorgyline, deprenyl, rasagiline), the latest generation of MAO inhibitors includes a wide variety of chemotypes obtained from synthetic compounds or natural products, such as chalcones, pyrazoles, chromones, coumarins, isatin derivatives, thiazolidindiones, and polyamine analogues . In particular, the most recent efforts have involved the development of reversible and MAO‐B‐selective compounds, such as safinamide ( K i ca.…”