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Exploration of a library of piperonylic acid-derived hydrazones possessing variable aryl functionalities as potent dual cholinesterase and monoamine oxidase inhibitors

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Abstract

A library of piperonylic acid-derived hydrazones possessing variable aryl moiety was synthesized and investigated for their multifunctional properties against cholinesterases (ChEs) and monoamine oxidases (MAOs). The in vitro enzymatic assay results revealed that the tested hydrazones have exhibited excellent cholinesterase inhibition profile. Compound 4i, (E)-N'-(2,3-dichlorobenzylidene)benzo[d][1,3]dioxole-5-carbohydrazide showed promising dual inhibitory profile against AChE (0.048 ± 0.007 μM), BChE (0.89 ± 0.018 μM), and MAO-B (0.95 ± 0.12 μM) enzymes. SAR exploration revealed that the truncation of the linker connecting both the aryl binding sites of the semicarbazone scaffold, by one atom, has relatively suppressed the AChE inhibitory potential. Kinetic studies disclosed that the compound 4i reversibly inhibited AChE enzyme in a competitive manner (Ki = 8.0 ± 0.076 nM), while it displayed a non-competitive and reversible inhibition profile against MAO-B (Ki = 9.6 ± 0.021 µM). Moreover, molecular docking studies of synthesized compounds against ChEs and MAOs provided the crucial molecular features that enable their close association and interaction with the target enzymes. All atomistic simulation studies confirmed the stable association of compound 4i within the active sites of AChE and MAO-B. In addition, theoretical ADMET prediction studies demonstrated the acceptable pharmacokinetic profile of the dual inhibitors. In summary, the attempted lead simplification study afforded a potent dual ChE–MAO-B inhibitor compound that merits further investigation.

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Acknowledgements

The first author (Pavan Kumar V.) is thankful to the Indian Institute of Technology (BHU) Varanasi, for providing a Teaching Assistantship. The support and the resources provided by ‘PARAM Shivay Facility’ under the National Supercomputing Mission, Government of India at the Indian Institute of Technology (BHU), Varanasi are gratefully acknowledged.

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  1. Pharmaceutical Chemistry Research Laboratory II, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, UP, 221005, India

    V. Pavan Kumar, M. S. Vishnu, Sandeep Kumar, Shivani Jaiswal & Senthil Raja Ayyannan

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  1. V. Pavan Kumar
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Kumar, V.P., Vishnu, M.S., Kumar, S. et al. Exploration of a library of piperonylic acid-derived hydrazones possessing variable aryl functionalities as potent dual cholinesterase and monoamine oxidase inhibitors. Mol Divers 27, 2465–2489 (2023). https://doi.org/10.1007/s11030-022-10564-9

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