Design, synthesis, and biological evaluation of novel benzimidazole derivatives as sphingosine kinase 1 inhibitor.

Autor: Khairat SHM; Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Cairo, Egypt., Omar MA; Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Cairo, Egypt., Ragab FAF; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt., Roy S; Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India., Turab Naqvi AA; Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany., Abdelsamie AS; Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Cairo, Egypt.; Department of Pharmacy, Saarland University, Saarbrücken, Germany., Hirsch AKH; Department of Pharmacy, Saarland University, Saarbrücken, Germany.; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt., Galal SA; Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Cairo, Egypt., Hassan MI; Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India., El Diwani HI; Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Cairo, Egypt.
Jazyk: angličtina
Zdroj: Archiv der Pharmazie [Arch Pharm (Weinheim)] 2021 Sep; Vol. 354 (9), pp. e2100080. Date of Electronic Publication: 2021 Jun 15.
DOI: 10.1002/ardp.202100080
Abstrakt: Sphingosine kinase 1 (SphK1) has emerged as an attractive drug target for different diseases. Recently, discovered SphK1 inhibitors have been recommended in cancer therapeutics; however, selectivity and potency are great challenges. In this study, a novel series of benzimidazoles was synthesized and evaluated as SphK1 inhibitors. Our design strategy is twofold: It aimed first to study the effect of replacing the 5-position of the benzimidazole ring with a polar carboxylic acid group on the SphK1-inhibitory activity and cytotoxicity. Our second aim was to optimize the structures of the benzimidazoles through the elongation of the chain. The enzyme inhibition potentials against all the synthesized compounds toward SphK1 were evaluated, and the results revealed that most of the studied compounds inhibited SphK1 effectively. The binding affinity of the benzimidazole derivatives toward SphK1 was measured by fluorescence binding and molecular docking. Compounds 33, 37, 39, 41, 42, 43, and 45 showed an appreciable binding affinity. Therefore, the SphK1-inhibitory potentials of compounds 33, 37, 39, 41, 42, 43, and 45 were studied and IC 50 values were determined, to reveal high potency. The study showed that these compounds inhibited SphK1 with effective IC 50 values. Among the studied compounds, compound 41 was the most effective one with the lowest IC 50 value and a high cytotoxicity on a wide spectrum of cell lines. Molecular docking revealed that most of these compounds fit well into the ATP-binding site of SphK1 and form hydrogen bond interactions with catalytically important residues. Overall, the findings suggest the therapeutic potential of benzimidazoles in the clinical management of SphK1-associated diseases.
(© 2021 Deutsche Pharmazeutische Gesellschaft.)
Databáze: MEDLINE
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