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Open AccessArticle

Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1

1
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
2
Department of Chemistry, Indian Institute of Technology, Palaj, Gandhinagar, Gujarat 382355, India
3
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Author contributed equally contributed to this work.
Pharmaceuticals 2020, 13(6), 118; https://doi.org/10.3390/ph13060118
Received: 13 May 2020 / Revised: 30 May 2020 / Accepted: 1 June 2020 / Published: 9 June 2020
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2.0)
Sphingosine kinase 1 (SphK1) is one of the well-studied drug targets for cancer and inflammatory diseases. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, selectivity and potency of first-generation inhibitors are great challenge. In search of effective SphK1 inhibitors, a set of small molecules have been designed and synthesized bearing urea, sulfonylurea, sulfonamide, and sulfonyltriurea groups. The binding affinity of these inhibitors was measured by fluorescence-binding assay and isothermal titration calorimetry. Compounds 1, 5, 6, and 7 showed an admirable binding affinity to the SphK1 in the sub-micromolar range and significantly inhibited SphK1 activity with admirable IC50 values. Molecular docking studies revealed that these compounds fit well into the sphingosine binding pocket of SphK1 and formed significant number of hydrogen bonds and van der Waals interactions. These molecules may be exploited as potent and selective inhibitors of SphK1 that could be implicated in cancer therapeutics after the required in vivo validation. View Full-Text
Keywords: sphingosine kinase-1; sphingosine-1-phosphate; cancer therapy; enzyme inhibition; kinase inhibitors; molecular docking; drug design and discovery sphingosine kinase-1; sphingosine-1-phosphate; cancer therapy; enzyme inhibition; kinase inhibitors; molecular docking; drug design and discovery
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MDPI and ACS Style

Roy, S.; Mahapatra, A.D.; Mohammad, T.; Gupta, P.; Alajmi, M.F.; Hussain, A.; Rehman, M.T.; Datta, B.; Hassan, M.I. Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1. Pharmaceuticals 2020, 13, 118.

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