Ethyl acetohydroxamate containing chalcones: Unearthing of a novel class of multitarget MAO-B inhibitors against Alzheimer’s disease

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 target prediction is 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. 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 substitutentin ring Aof ethyl acetohydroxamate-chalcones (L1-L9), F atom at pposition (L3) showed highest inhibitory effect against hMAO-B. This result supports the uniqness and bizarre behavior of Fluoorine atom. Moerover, chalcones L3, L4, L9, L11, and L12 showed potential AChE inhibitory effect with IC50 values 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.