Ethoxylated Head of Chalcones as a New Class of Multi-Targeted MAO Inhibitors

A series of eleven ethoxysubstituted chalcones (E1-E11) were synthesized and investigated for their inhibitory potential towards human recombinant monoamine oxidase A and B (hMAO−A and hMAO−B, respectively) and acetylcholinesterase (AChE). IC50 values of 4.63 ± 0.15 and 0.053 ± 0.003 μM were obtained for MAO−A and MAO−B, respectively, by the most interesting compound (2E)-1-(4-ethoxyphenyl)-3-(4-fluorophenyl)prop-2-en-1-one (E7), and it was characterized by a high selectivity index (SI=87.4) for MAO−B. Inhibitions by E7 against MAO−A and MAO−B were recovered (75.9 and 74.5%, respectively) to near the levels of reversible references (77.1 and 77.4%, respectively). The inhibition modes of E7 for MAO−A and MAO−B were competitive with Ki values of 2.65 ± 0.064 and 0.011 ± 0.0011 μM, respectively. Compounds (2E)-1-(4-ethoxyphenyl)-3-(4-ethylphenyl) prop-2-en-1-one (E10) and (2E)-1-(4-ethoxyphenyl)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one (E11) showed good inhibitions against AChE with IC50 values of 2.86 ± 0.041 and 3.23 ± 0.0073 μM, respectively. A combined molecular docking/MM-GBSA approach was used that employed quantum mechanics (QM) partial charges; this technique revealed the molecular rationale behind the observed MAO−B selectivity for this molecular series. Taken together, these results indicate that E7 is a potent, selective and reversible competitive inhibitor of MAO−B with moderately potent AChE inhibitory activity that has potential as a multi-targeting drug.