Synthesis of a series of unsaturated ketone derivatives as selective and reversible monoamine oxidase inhibitors.
We have synthesized three categories of α,β-unsaturated carbonyl derivatives and evaluated their MAO-A and MAO-B inhibitory activities. Among them, compound 10b including α,β-unsaturated ketone group showed the most potent and selective MAO-B inhibitory activity (IC₅₀ human MAO-B 16 nM, >6000-fold selective vs MAO-A) and compound 10b exhibited good reversibility compared with selegiline, a well-known irreversible MAO-B inhibitor. However, both α,β-unsaturated amide and ester derivatives exhibited weaker MAO-B inhibition potencies. The docking studies provided insights into the possible binding modes and the key interaction sites of the synthesized MAO-B inhibitors.
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, 5 Hwarang-ro, 14-gil, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Ji Won
JW
Choi
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, 5 Hwarang-ro, 14-gil, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
Bo Ko
BK
Jang
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, 5 Hwarang-ro, 14-gil, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Nam-chul
NC
Cho
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, 5 Hwarang-ro, 14-gil, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Jong-Hyun
JH
Park
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, 5 Hwarang-ro, 14-gil, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Seul Ki
SK
Yeon
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, 5 Hwarang-ro, 14-gil, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Eun Ji
EJ
Ju
Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.
Yong Sup
YS
Lee
Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Gyoonhee
G
Han
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, 5 Hwarang-ro, 14-gil, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biological Chemistry, University of Science and Technology, Daejeon 305-350, Republic of Korea.
Ae Nim
AN
Pae
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, 5 Hwarang-ro, 14-gil, Seongbuk-gu, Seoul 136-791, Republic of Korea.
Dong Jin
DJ
Kim
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, 5 Hwarang-ro, 14-gil, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biological Chemistry, University of Science and Technology, Daejeon 305-350, Republic of Korea. Electronic address: kdpark@kist.re.kr.
Ki Duk
KD
Park
D001665:Binding Sites; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D016166:Free Radical Scavengers; D007659:Ketones; D008996:Monoamine Oxidase Inhibitors; D006861:Hydrogen Peroxide; D008995:Monoamine Oxidase
Chalcone; MAO-B inhibitor; Monoamine oxidase; Reversible inhibitor; α,β-Unsaturated carbonyl derivatives