Background: Chalcones are considered as the selective scaffold for the inhibition of MAO-B.
Objectives: A previously synthesized ethyl acetohydroxamate-chalcones (L1-L22) were studied for
their inhibitory activities against human recombinant monoamine oxidase A and B (hMAO-A and
hMAO-B, respectively) and acetylcholinesterase (AChE) as multi-target directed ligands for the
treatment of Alzheimer’s Disease (AD).
Methods: Enzyme inhibition studies of MAO-A, MAO-B and AChE is carried out. Computational
studies such as Molecular docking, Molecular Mechanics/Generalized Born Surface Area calculations,
ADMET prediction, and protein target prediction are also performed.
Results: Among the screened compounds, compound L3 has most potent hMAO-B inhibition with an
IC50 value of 0.028 ± 0.0016 µM, and other compounds, L1, L2, L4, L8, L12, and L21 showed significant
potent hMAO-B inhibition with IC50 values of 0.051 ± 0.0014, 0.086 ± 0.0035, 0.036 ± 0.0011,
0.096 ± 0.0061, 0.083 ± 0.0016, and 0.038 ± 0.0021 µM, respectively. On the other hand, among the
tested compounds, compound L13 showed highest hMAO-A inhibition with an IC50 value of 0.51±
0.051 µM and L9 has a significant value of 1.85 ± 0.045 µM. However, the compounds L3 and L4 only
showed high selectivities for hMAO-B with Selectivity Index (SI) values of 621.4 and 416.7, respectively.
Among the substituents in ring A of ethyl acetohydroxamate-chalcones (L1-L9), F atom at
p-position (L3) showed highest inhibitory effect against hMAO-B. This result supports the uniqness
and bizarre behavior of fluorine. Moreover, chalcones L3, L4, L9, L11, and L12 showed potential
AChE inhibitory effect with IC50 values of 0.67, 0.85, 0.39, 0.30, and 0.45 µM, respectively. Inhibitions
of hMAO-B by L3 or L4 were recovered to the level of the reversible reference (lazabemide),
and were competitive with Ki values of 0.0030 ± 0.0002 and 0.0046 ± 0.0005 µM, respectively. Inhibitions
of AChE by L3 and L11 were of the competitive and mixed types with Ki values of 0.30 ±
0.044 and 0.14 ± 0.0054 µM, respectively.
Conclusion: The studies indicated that L3 and L4 are considered to be promising multitarget drug
molecules with potent, selective, and reversible competitive inhibitors of hMAO-B and with highly
potent AChE inhibitory effect.