期刊
CHEMMEDCHEM
卷 15, 期 17, 页码 1629-1633出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202000305
关键词
blood-brain barrier; cytotoxicity; kinetics; monoamine oxidase; morpholine; reversibility
资金
- Deanship of Scientific Research (DSR) at King Khalid University (KKU), Abha, Kingdom of Saudi Arabia [G.R.P-23-41]
The general blueprint for the design of monoamine oxidase-B (MAO-B) inhibitors has been based on two phenyl or heteronuclei linked via a spacer of appropriate length. In this study, 1-[4-(morpholin-4-yl)phenyl]-5-phenylpenta-2,4-dien-1-one (MO10) was prepared by the condensation of 4 '-morpholinoacetophenone and cinnamaldehyde in basic alcoholic medium. MO10 was assessed for inhibitory activity against two human MAO isoforms, MAO-A and MAO-B. Interestingly, MO10 showed a remarkable inhibition against MAO-B with an IC(50)value of 0.044 mu M along with a selectivity index of 366.13. The IC(50)value was better than that of lazabemide (IC(50)value of 0.063 mu M), which was used as a reference. Kinetics studies revealed that MO10 acted as a competitive inhibitor of MAO-B, with aK(i)value of 0.0080 mu M. The observation of recovery of MAO-B inhibition, compared to reference levels showed MO10 to be a reversible inhibitor. MTT assays showed that MO10 was nontoxic to normal VERO cells with an IC(50)value of 195.44 mu g/mL. SwissADME predicted that MO10 provided advantageous pharmacokinetics profiles for developing agents acting on the central nervous system, that is, high passive human gastrointestinal absorption and blood-brain barrier permeability. Molecular docking simulations showed that MO10 properly entered the aromatic cage formed by Y435, Y398, and FAD of the active site of MAO-B. On the basis of these results, MO10 can be considered a promising starting compound in development of agents for the treatment of various neurodegenerative disorders.
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