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Design, synthesis, and molecular modeling of new 3(2H)-pyridazinone derivatives as acetylcholinesterase/butyrylcholinesterase inhibitors

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Abstract

Inhibition of cholinesterases is an effective method to curb Alzheimer’s disease, a progressive and fatal neurological disorder. A series of 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(p-substituted benzalhidrazone) derivatives were designed, synthesized, and their inhibitory effects on acetylcholinesterase and butyrylcholinesterase were evaluated in pursuit of potent dual inhibitors. We obtained our compounds by the reaction of various substituted/nonsubstituted benzaldehydes with 6-[4-(3,4-dichlorophenyl)piperazine-1-yl]-3(2H)-pyridazinone-2-yl acetohydrazide and determined their anticholinesterase activities according to the Ellman’s method. 5f and 5i showed 75.52 and 71.72% acetylcholinesterase inhibition at 100 µg/ml, respectively. 5h and 5f, on the other hand, were the best butyrylcholinesterase inhibitors with 67.16 and 62.03% inhibition at the same concentration, respectively. 5f emerged as a potent dual cholinesterase inhibitor. Through molecular docking studies we predicted the inhibition mechanism of 5f for both enzymes in comparison with our previous derivatives, which differ in inhibition potency, and tried to get insights into the factors that affect receptor affinity in molecular level.

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Acknowledgements

This study was funded by the Research Foundation of İnönü University (2013/94).

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Authors and Affiliations

  1. Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Inonu University, Malatya, 44280, Turkey

    Zeynep Özdemir & Arzu Karakurt

  2. Kayseri Vocational School, Department of Biomedical Devices and Technologies, Erciyes University, Kayseri, 38039, Turkey

    Hayriye Yılmaz

  3. Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Hacettepe University, Ankara, 06100, Turkey

    Suat Sarı

  4. Faculty of Pharmacy, Department of Pharmacognosy, Gazi University, Ankara, 06100, Turkey

    Fatma Sezer Şenol

  5. Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Gazi University, Ankara, 06100, Turkey

    Mehtap Uysal

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  1. Zeynep Özdemir
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Özdemir, Z., Yılmaz, H., Sarı, S. et al. Design, synthesis, and molecular modeling of new 3(2H)-pyridazinone derivatives as acetylcholinesterase/butyrylcholinesterase inhibitors. Med Chem Res 26, 2293–2308 (2017). https://doi.org/10.1007/s00044-017-1930-x

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