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

Chemical biology & drug design 2023 Aug

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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. © 2023 John Wiley & Sons Ltd.

Citation

Ashutosh Kumar Singh, Seong-Min Kim, Jong Min Oh, Mohamed A Abdelgawad, Mohammed M Ghoneim, T M Rangarajan, Sunil Kumar, Sachithra Thazhathuveedu Sudevan, Daniela Trisciuzzi, Orazio Nicolotti, Hoon Kim, Bijo Mathew. Exploration of a new class of monoamine oxidase B inhibitors by assembling benzyloxy pharmacophore on halogenated chalcones. Chemical biology & drug design. 2023 Aug;102(2):271-284