Exploration of a new class of monoamine oxidase B inhibitors by assembling benzyloxy pharmacophore on halogenated chalcones

by Selleckchem | Feb 14 2024

Eight derivatives of benzyloxy-derived halogenated chalcones (BB1-BB8) were synthesized and tested for their ability to inhibit monoamine oxidases (MAOs). MAO-A was less efficiently inhibited by all compounds than MAO-B. Additionally, the majority of the compounds displayed significant MAO-B inhibitory activities at 1 μM with residual activities of less than 50%. With an IC50 value of 0.062 μM, compound BB4 was the most effective in inhibiting MAO-B, followed by compound BB2 (IC50 = 0.093 μM). The lead molecules showed good activity than the reference MAO-B inhibitors (Lazabemide IC50 = 0.11 μM and Pargyline Pargyline IC50 = 0.14). The high selectivity index (SI) values for MAO-B were observed in compounds BB2 and BB4 (430.108 and 645.161, respectively). Kinetics and reversibility experiments revealed that BB2 and BB4 were reversible competitive MAO-B inhibitors with Ki values of 0.030 ± 0.014 and 0.011 ± 0.005 μM, respectively. Swiss target prediction confirmed the high probability in the targets of MAO-B for both compounds. Hypothetical binding mode revealed that the BB2 or BB4 is similarly oriented to the binding cavity of MAO-B. Based on the modelling results, BB4 showed a stable confirmation during the dynamic simulation. From these results, it was concluded that BB2 and BB4 were potent selective reversible MAO-B inhibitors and they can be considered drug candidates for treating related neurodegenerative diseases such as Parkinson's disease.

Comments:

It seems like you're discussing the synthesis and testing of derivatives of benzyloxy-derived halogenated chalcones (BB1-BB8) as potential inhibitors of monoamine oxidases (MAOs), specifically focusing on their effects on MAO-A and MAO-B.

The key findings from your description are:
1. **Inhibition of MAOs:** All compounds showed less inhibition of MAO-A compared to MAO-B.
2. **MAO-B Inhibition:** Most compounds displayed significant MAO-B inhibitory activities at 1 μM, with IC50 values indicating strong inhibition.
3. **Effectiveness of Compounds:** BB4 exhibited the highest effectiveness in inhibiting MAO-B (IC50 = 0.062 μM), followed by BB2 (IC50 = 0.093 μM).
4. **Comparison with Reference Inhibitors:** BB2 and BB4 showed better activity than the reference MAO-B inhibitors Lazabemide (IC50 = 0.11 μM) and Pargyline (IC50 = 0.14 μM).
5. **Selectivity Index:** BB2 and BB4 exhibited high selectivity index values for MAO-B (430.108 and 645.161, respectively).
6. **Kinetics and Reversibility:** BB2 and BB4 were identified as reversible competitive MAO-B inhibitors with Ki values of 0.030 ± 0.014 and 0.011 ± 0.005 μM, respectively.
7. **Target Prediction and Binding Mode:** Swiss target prediction supported MAO-B as a probable target for both compounds. The hypothetical binding mode suggested a similar orientation of BB2 and BB4 in the MAO-B binding cavity.
8. **Stability and Modeling:** BB4 showed stable confirmation during dynamic simulation.

The conclusion drawn from these results is that BB2 and BB4 are potent, selective, reversible MAO-B inhibitors, making them potential drug candidates for treating neurodegenerative diseases like Parkinson's disease.

This research signifies a promising direction in drug development, particularly in addressing neurodegenerative conditions by targeting specific enzymes like MAO-B. The findings regarding the potency, selectivity, and reversibility of BB2 and BB4 make them promising candidates for further studies and potential therapeutic applications.