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Ligand-based designing of DPP-4 inhibitors via hybridization; synthesis, docking, and biological evaluation of pyridazine-acetohydrazides

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Abstract

A series of novel pyridazine-acetohydrazide hybrids were designed, synthesized, and evaluated for their in vitro and in vivo antihyperglycemic activity. In this context, pyridazine-acetohydrazides (6a–6p) were synthesized by coupling substituted aldehyde with 2-(5-cyano-6-oxo-3,4-diphenylpyridazine-1-6H-yl) acetohydrazide, which was prepared via the reaction of pyridazine ester with hydrazine hydrate. The molecular docking study was carried out to examine the binding affinities and interaction of designed compounds against the DPP-4 enzyme. Compounds 6e, 6f, 6l, and 6n exhibited interaction with active residue. In silico ADMET properties, and toxicity studies corroborated that compounds were found to have good bioavailability and less toxic. The synthesized compounds were further estimated for in vitro DPP-4 activity. Compounds 6e and 6l were found as the most effective DPP-4 inhibitor in this series with IC50 values (6.48, 8.22 nM) when compared with sitagliptin (13.02 nM). According to the toxicity assay compound, 6l showed very less toxicity at a higher concentration so further selected for the in vivo antihyperglycemic activity.

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Acknowledgements

The authors are thankful to the Molecular Endocrinology and Toxicology Lab (MET Lab), Department of Zoology, Banaras Hindu University for providing the facility for biological studies. All animal studies performed at MET lab were supported by SERB (ECR/2017/000685) and UGC-BSR, New Delhi (F.30-370/2017-BSR) Grant to RKS.

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Authors and Affiliations

  1. Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India

    Manisha Nidhar, Vipin Kumar, Brijesh Kumar Yadav & Ashish Kumar Tewari

  2. Molecular Endocrinology and Toxicology Lab (MET Lab), Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India

    Archisman Mahapatra, Priya Gupta & Rahul Kumar Singh

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  1. Manisha Nidhar
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Nidhar, M., Kumar, V., Mahapatra, A. et al. Ligand-based designing of DPP-4 inhibitors via hybridization; synthesis, docking, and biological evaluation of pyridazine-acetohydrazides. Mol Divers 27, 2729–2740 (2023). https://doi.org/10.1007/s11030-022-10577-4

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