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Evaluation of 2-amino-6-nitrobenzothiazole derived hydrazones as acetylcholinesterase inhibitors: in vitro assays, molecular docking and theoretical ADMET prediction

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Abstract

Acetylcholinesterase (AChE) is an important target for the treatment of neurodegenerative disorders. A library of 2-amino-6-nitrobenzothiazole-derived hydrazones was evaluated as inhibitors of AChE. The compounds inhibited AChE with IC50 values in nanomolar to micromolar range. N′-(5-chloro-2-oxoindolin-3-ylidene)-2-(6-nitrobenzothiazol-2-ylamino)acetohydrazide (35) showed strong inhibitory activity against AChE (IC50 = 0.0035 ± 0.005 µM), which was found to be ~0.6-fold active compared to donepezil and ~6.43-fold stronger compared to tacrine. Kinetic studies revealed that compound 35 exhibited a mixed type and reversible mode of enzyme inhibition. SAR studies disclosed several structural aspects significant for potency of these analogs. Molecular docking simulations and binding pose analysis of docked conformations revealed the significance of cumulative effects of hydrogen bonding and π–π interactions for effective stabilization of virtual ligand–AChE complexes. Conformational analysis of lead AChE inhibitor molecules led to the proposal of a five-point pharmacophore model essential for the AChE inhibition. Further, compound 35 presented antioxidant activity higher than ascorbic acid in the in vitro DPPH radical scavenging assay. Additionally, in silico molecular and ADMET properties of the synthesized compounds were predicted to explore their drug likeness for potential oral use as antineurodegenerative agents.

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Acknowledgements

The authors thank Dr. Sairam Krishnamurthy, Associate Professor of Pharmacology, Department of Pharmaceutical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi for his invaluable assistance in pharmacological screening. First author (Rati K. P. Tripathi) thanks the Indian Council of Medical Research, New Delhi (India) for the award of Senior Research Fellowship.

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

    Rati K. P. Tripathi & Senthil Raja Ayyannan

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  1. Rati K. P. Tripathi
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  2. Senthil Raja Ayyannan
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Correspondence to Senthil Raja Ayyannan.

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Tripathi, R.K.P., Ayyannan, S.R. Evaluation of 2-amino-6-nitrobenzothiazole derived hydrazones as acetylcholinesterase inhibitors: in vitro assays, molecular docking and theoretical ADMET prediction. Med Chem Res 27, 709–725 (2018). https://doi.org/10.1007/s00044-017-2095-3

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