Inhibition of monoamine oxidase by 8-phenoxymethylcaffeine derivatives.
A recent study has reported that a series of 8-benzyloxycaffeines are potent and reversible inhibitors of both human monoamine oxidase (MAO) isoforms, MAO-A and -B. In an attempt to discover additional caffeine derivatives with potent MAO inhibitory activities, and to contribute to the known structure-activity relationships of MAO inhibition by caffeine derived compounds, the present study investigates the MAO inhibitory potencies of series of 8-phenoxymethylcaffeine and 8-[(phenylsulfanyl)methyl]caffeine derivatives. The results document that the 8-phenoxymethylcaffeine derivatives act as potent reversible inhibitors of MAO-B, with IC(50) values ranging from 0.148 to 5.78 μM. In contrast, the 8-[(phenylsulfanyl)methyl]caffeine derivatives were found to be weak inhibitors of MAO-B, with IC(50) values ranging from 4.05 to 124 μM. Neither the 8-phenoxymethylcaffeine nor the 8-[(phenylsulfanyl)methyl]caffeine derivatives exhibited high binding affinities for MAO-A. While less potent than the 8-benzyloxycaffeines as MAO-B inhibitors, this study concludes that 8-phenoxymethylcaffeines may act as useful leads for the design of MAO-B selective inhibitors. Such compounds may find application in the therapy of neurodegenerative disorders such as Parkinson's disease. Using molecular docking experiments, this study also proposes possible binding orientations of selected caffeine derivatives in the active sites of MAO-A and -B.
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Thokozile
T
Okaecwe
Abraham J
AJ
Swanepoel
Anél
A
Petzer
Jacobus J
JJ
Bergh
Jacobus P
JP
Petzer
D001665:Binding Sites; D002110:Caffeine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D020134:Catalytic Domain; D003198:Computer Simulation; D006801:Humans; D007700:Kinetics; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D008996:Monoamine Oxidase Inhibitors; D020033:Protein Isoforms; D011994:Recombinant Proteins; D002110:Caffeine; D008995:Monoamine Oxidase