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Design, synthesis, and evaluation of novel hydrazide hydrochlorides of 6-aminopyrazolo[1,5-a]pyrimidine-3-carboxamides as potent Aurora kinase inhibitors

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Abstract

The Aurora kinases play a key role in mitosis and are overexpressed in multiple human tumor types; there has been considerable interest in developing Aurora kinase inhibitors as antitumor agents, particularly Aurora A and Aurora B kinases. A series of novel hydrazide hydrochlorides of pyrazolo[1,5-a]pyrimidine carboxamides were designed and synthesized and their inhibitory activities against Aurora kinases were evaluated. Some of the tested compounds exhibited low micromolar to nanomolar activity with respect to the inhibition of Aurora A kinase. The most potent compound in this series was found to be a potent inhibitor of Aurora A in an HTRF enzymatic assay with an IC50 as low as 23 nM. A structure–activity relationship study indicated that halogen substitution in the benzene ring of amide plays an important role in kinase inhibitory potency.

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Acknowledgements

We are thankful to Anthem Biosciences management, Anthem Biosciences, Bangalore, India, for their invaluable support and allocation of resources for this work. We would like to thank Analytical chemistry team, Department of Analytical Chemistry, Anthem Biosciences, Bangalore, India, for having carried out all the analytical work. Also, we would like to thank molecular biology team, Department of Molecular Biology, Anthem Biosciences, Bangalore, India, for executing the Aurora Kinase activity studies.

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Authors and Affiliations

  1. Anthem Biosciences Pvt. Ltd., # 49, Bommasandra Industrial Area, Bommasandra, Bangalore, Karnataka, 560 099, India

    A. K. Ajeesh Kumar, Ganesh Sambasivam & Peter Serjious Lakra

  2. Department of PG Studies and Research in Industrial Chemistry, School of Chemical Sciences, Kuvempu University, Shankaraghatta, Shimoga, Karnataka, 577 451, India

    Yadav D. Bodke

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  1. A. K. Ajeesh Kumar
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  2. Yadav D. Bodke
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Correspondence to A. K. Ajeesh Kumar.

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Kumar, A.K.A., Bodke, Y.D., Sambasivam, G. et al. Design, synthesis, and evaluation of novel hydrazide hydrochlorides of 6-aminopyrazolo[1,5-a]pyrimidine-3-carboxamides as potent Aurora kinase inhibitors. Monatsh Chem 148, 1767–1780 (2017). https://doi.org/10.1007/s00706-017-1943-7

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