Design and synthesis of new pyrazolylbenzimidazoles as sphingosine 1-kinase inhibitors

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Abstract Sphingosine-1 Kinase (SphK-1) is one of the important enzymes of phospholipids and it is inhibition is one of the therapeutic strategies for different diseases. SphK1 over expression is observed in different types of cancer that indicating its important role in tumor growth. In search of effective SphK-1 inhibitors, a new series of pyrazolylbenzimidazoles was synthesized and evaluated as sphingosine1-kinase (Sphk-1) inhibitors. In order to evaluate the binding affinities of all the synthesized compounds, all compounds were subjected to docking analysis and fluorescence quenching. The results indicated that there is a consistency between the docking and the fluorescence quenching results which revealed that compounds 47 and 48 exhibited significant decrease in the fluorescence intensity of SphK1 as well as they formed stable protein–ligand complexes. In addition, Enzyme inhibition assay was performed and showed effective inhibitory potential towards SphK-1. Moreover, IC50 values was calculated and displayed that compounds 47 and 48 were the most promising compounds. In addition, antiproliferation study for all the synthesized compounds was performed against NCI 60-cell line panel. The target compounds 47 and 48 demonstrated effective antitumor activity inhibitory potential to the SphK-1. Most of these compounds fit well into the ATP-binding site of SphK1 and form significant hydrogen-bonding interactions with catalytically relevant residues as predicted by molecular docking. In this article, insight has been given for the importance of pyrazolylbenzimidazoles as Sphk1 inhibitors and the perspectives that they hold for future research.

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