Rapid synthesis of flavone-based monoamine oxidase (MAO) inhibitors targeting two active sites using click chemistry.
A new library of flavone derivatives targeting two active sites of monoamine oxidases ("aromatic cage" and substrate cavity) were designed and synthesized using click chemistry (CuAAC reaction) between 6-N3-2-phenyl chromones (Az1-Az2) and a series of alkynes (k1-k20). Their inhibitory activities against MAO isoforms (MAO-A and MAO-B) are evaluated. Compounds with fluorine, amide bonds, or amino bonds have shown better inhibition. The most potent flavone MAO inhibitor studied is Az2k19 (1.6 μm for MAO-A, 2.1 μm for MAO-B), while Az1k15 and Az2k15 displayed better selectivity toward MAO-B (SI > 10). Docking studies are in accordance with our hypothesis that these inhibitors are most likely located at both the substrate cavity and the "aromatic cage". Our results show that it is considerable to develop new MAO inhibitors from C6 substitution of flavone derivatives and that these compounds are also potential for the treatment of diseases associated with MAOs.
Institute of Bioengineering, Zhejiang University of Technology, Zhejiang, China.
Wei Zhen
WZ
Jia
Institute of Bioengineering, Zhejiang University of Technology, Zhejiang, China.
Feng
F
Cheng
Institute of Bioengineering, Zhejiang University of Technology, Zhejiang, China.
Yin Jun
YJ
Zhang
Institute of Bioengineering, Zhejiang University of Technology, Zhejiang, China.
Jin Yan
JY
Ge
Department of Chemistry, National University of Singapore, Singapore, Singapore.
Shao Q
SQ
Yao
Institute of Bioengineering, Zhejiang University of Technology, Zhejiang, China.
Qing
Q
Zhu
D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D057930:Click Chemistry; D047309:Flavones / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D062105:Molecular Docking Simulation; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
D047309:Flavones; D008996:Monoamine Oxidase Inhibitors
click chemistry; flavones; low cytotoxicity; molecular docking; monoamine oxidase inhibitors