12 research outputs found
Structure-Activity Relationship Analysis of 3-Phenylcoumarin-Based Monoamine Oxidase B Inhibitors
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 mu M. 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
Renal Growth in Children with Severe Vesicoureteral Reflux: 10-year Prospective Study of Medical and Surgical Treatment
Erratum to: Cyclosporine A vs. methylprednisolone for HenochâSchönlein nephritis: a randomized trial
Blocking oestradiol synthesis pathways with potent and selective coumarin derivatives
A comprehensive set of 3-phenylcoumarin analogues with polar substituents was synthesised for blocking
oestradiol synthesis by 17-b-hydroxysteroid dehydrogenase 1 (HSD1) in the latter part of the sulphatase
pathway. Five analogues produced 62% HSD1 inhibition at 5 mM and, furthermore, three of them produced
68% inhibition at 1 mM. A docking-based structure-activity relationship analysis was done to determine
the molecular basis of the inhibition and the cross-reactivity of the analogues was tested against
oestrogen receptor, aromatase, cytochrome P450 1A2, and monoamine oxidases. Most of the analogues
are only modestly active with 17-b-hydroxysteroid dehydrogenase 2 â a requirement for lowering effective
oestradiol levels in vivo. Moreover, the analysis led to the synthesis and discovery of 3-imidazolecoumarin
as a potent aromatase inhibitor. In short, coumarin core can be tailored with specific ring and polar moiety
substitutions to block either the sulphatase pathway or the aromatase pathway for treating breast cancer
and endometriosis.peerReviewe
Structure-Activity Relationship Analysis of 3-phenylcoumarin-Based Monoamine Oxidase B Inhibitors
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 nMâ1 ÎŒM. 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.peerReviewe