Design of enamides as new selective monoamine oxidase-B inhibitors

Abstract

Objectives To develop of new class of selective and reversible MAO-B inhibitors from enamides. Methods Syntheses of the titled derivatives (AD1-AD11) were achieved by reacting cinnamoyl chloride and various primary and secondary amines in basic medium. All eleven compounds were investigated for in vitro inhibitory activities against recombinant human MAO-A and MAO-B. The reversibilities of lead compound inhibitions were analysed by dialysis. MTT assays of lead compounds were performed using normal VERO cell lines. Key findings Compounds AD3 and AD9 exhibited the greatest inhibitory activity against MAO-B with IC 50 values of 0.11 and 0.10 µM, respectively, and were followed by AD2 and AD1 (0.51 and 0.71 µM, respectively). Most of the compounds weakly inhibited MAO-A, with the exceptions AD9 and AD7, which had IC 50 values of 4.21 and 5.95 µM, respectively. AD3 had the highest selectivity index (SI) value for MAO-B (>363.6) and was followed by AD9 (SI 42.1). AD3 and AD9 were found to be competitive inhibitors of MAO-B with K i values of 0.044 AE 0.0036 and 0.039 AE 0.0047 µM, respectively. Reversibility experiments showed AD3 and AD9 were reversible inhibitors of MAO-B; dialysis restored the activity of MAO-B to the reference level. MTT assays revealed AD3 and AD9 were non-toxic to normal VERO cell lines with IC 50 values of 153.96 and 194.04 µg/ml, respectively. Computational studies provided hypothetical binding modes for AD3 and AD9 in the binding cavities of MAO-A and MAO-B. Conclusions These results encourage further studies on the enamide scaffold as potential drug candidates for the treatment of Alzheimer's and Parkinson's diseases.

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 results were coincided to the studies that the rational design of two phenyl/heteroaryl rings connected via a short linker could lead to potent inhibitors targeting MAO-B and MAO-A. [31,32] Recently, Mathew et al reported that fluorinated morpholine-based chalcones (f1-f3) exhibited potent inhibitory activity and high SI towards recombinant human MAO-B (IC 50 = 0.21 to 0.087 μM; SI = 47.6 to 517.2). [24] The molecular selectivity could be also modulated on the basis of electron donating and withdrawing substitutions on the rings and depended on the length and the degree of conjugation of linker.…”

“…Comparatively, it was less toxic than our previous reported compounds. [32] The therapeutic potential of the compound might be suitable with a low toxic profile on the normal cells.…”

Selected 1,3‐Benzodioxine‐Containing Chalcones as Multipotent Oxidase and Acetylcholinesterase Inhibitors

“…Residual activities were determined before (A U ) (i. e., undialyzed) and after (A D ) dialyzing and compared to controls (i. e., without inhibitor). [41] Inhibitions of MAO-A by CD3 and CD8 were substantially recovered from 39 % (A U ) to 90 % (A D ), and from 43 % to 63 %, respectively, and these values were similar to those obtained for the reversible inhibitor toloxatone (39 to 91 % and 35 to 90 %, respectively) ( Figures 2A & 2B). Dialysis recovered inhibition of MAO-B by CD8 from 42 % (A U ) to 80 % (A D ), and this was similar to that observed for the reversible inhibitor lazabemide (42 to 81 %) ( Figure 2C).…”

“…Dialysis experiments were performed by preincubating enzyme and inhibitors, i. e., MAO‐A inhibitions by CD3 and CD8 , of MAO‐B by CD8 , and of AChE by CD10 , (or references) at ∼2×IC 50 in 0.1 M sodium phosphate buffer (pH 7.2) for 30 min and dialyzing for 6 h (with a buffer change after 3 h) with stirring. Residual activities were determined before (A U ) (i. e., undialyzed) and after (A D ) dialyzing and compared to controls (i. e., without inhibitor) [41] . Inhibitions of MAO‐A by CD3 and CD8 were substantially recovered from 39 % (A U ) to 90 % (A D ), and from 43 % to 63 %, respectively, and these values were similar to those obtained for the reversible inhibitor toloxatone (39 to 91 % and 35 to 90 %, respectively) (Figures 2A & 2B).…”

Development of Halogenated Pyrazolines as Selective Monoamine Oxidase-B Inhibitors: Deciphering via Molecular Dynamics Approach

“…In the exploration of novel, selective, and reversible MAO-B inhibitors, a general blueprint of drug design has been widely accepted recently, and it consists of a molecular framework of two hydrophobic rings of phenyl/heteroaryl, which are separated by an electron-rich and flexible short spacer unit ( Figure 1 ) [ 11 ]. Many of the molecules from this diverse class, such as pyrazolines, enamides, carboxamides, and α, β-unsaturated ketones, were identified as potent MAO-B inhibitors [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. The presence of a rotatable bond and electron-rich Michael acceptor unit in the spacer can efficiently make appropriate orientations and binding affinities in the entrance and substrate cavity of MAO-B.…”