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

Abstract

A series of eleven ethoxysubstituted chalcones (E1-E11) were synthesized and investigated for their inhibitory potential towards human recombinant monoamine oxidase A and B (hMAOÀ A and hMAOÀ B, respectively) and acetylcholinesterase (AChE). IC 50 values of 4.63 � 0.15 and 0.053 � 0.003 μM were obtained for MAOÀ A and MAOÀ 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 MAOÀ B. Inhibitions by E7 against MAOÀ A and MAOÀ 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 MAOÀ A and MAOÀ B were competitive with K i values of 2.65 � 0.064 and 0.011 � 0.0011 μM, respectively. Compounds (2E)-1-(4ethoxyphenyl)-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 IC 50 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 MAOÀ B selectivity for this molecular series. Taken together, these results indicate that E7 is a potent, selective and reversible competitive inhibitor of MAOÀ B with moderately potent AChE inhibitory activity that has potential as a multitargeting drug

A New Potent and Selective Monoamine Oxidase‐B Inhibitor with Extended Conjugation in a Chalcone Framework: 1‐[4‐(Morpholin‐4‐yl)phenyl]‐5‐phenylpenta‐2,4‐dien‐1‐one

“…The interactions occurring between MAO-B and MO10, whose styryl group faced the FAD and interacted with Y435, were similar to those already proposed in the published reports, and could be crucial for addressing the inhibition of MAO-B. [43][44][45][46] Conversely, the styryl group did not reach the aromatic cage of MAO-A, made by FAD, Y407 and Y444.…”

Design of enamides as new selective monoamine oxidase-B inhibitors

“…Time‐dependencies, reversibilities and kinetic studies were performed on the most potent MAO‐B inhibitors, as previously described. [ 41,42 ] Kinetic experiments were carried out at five concentrations of the substrates and three inhibitor concentrations. We analysed the data using Excel program and obtained their R 2 scores for the lines.…”

An Update of Synthetic Approaches and Structure‐Activity Relationships of Various Classes of Human MAO‐B Inhibitors

“…The ethoxylated chalcones ( 12 ) with fluoro group are more selective for MOA‐B inhibitory activity with SI=87.4 and this compound showed comparative activity with that of standard irreversible inhibitor (pargyline) (Figure 7). The synthesis was carried out by Claisen‐Schmidt condensation between p ‐substituted acetophenones and variedly substituted aromatic aldehydes in basic medium as shown in the Figure 4 [58–60] …”