Structural Investigations on 2-Amidobenzimidazole Derivatives as New Inhibitors of Protein Kinase CK1 Delta.

Autor: Calenda S; Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Via Ugo Schiff, 6, 50019 Florence, Italy., Catarzi D; Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Via Ugo Schiff, 6, 50019 Florence, Italy., Varano F; Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Via Ugo Schiff, 6, 50019 Florence, Italy., Vigiani E; Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Via Ugo Schiff, 6, 50019 Florence, Italy., Volpini R; Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy., Lambertucci C; Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy., Spinaci A; Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy., Trevisan L; Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy., Grieco I; Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy., Federico S; Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy., Spalluto G; Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy., Novello G; Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy., Salmaso V; Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy., Moro S; Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy., Colotta V; Section of Pharmaceutical and Nutraceutical Sciences, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Via Ugo Schiff, 6, 50019 Florence, Italy.
Jazyk: angličtina
Zdroj: Pharmaceuticals (Basel, Switzerland) [Pharmaceuticals (Basel)] 2024 Apr 07; Vol. 17 (4). Date of Electronic Publication: 2024 Apr 07.
DOI: 10.3390/ph17040468
Abstrakt: Protein kinase CK1δ (CK1δ) is a serine-threonine/kinase that modulates different physiological processes, including the cell cycle, DNA repair, and apoptosis. CK1δ overexpression, and the consequent hyperphosphorylation of specific proteins, can lead to sleep disorders, cancer, and neurodegenerative diseases. CK1δ inhibitors showed anticancer properties as well as neuroprotective effects in cellular and animal models of Parkinson's and Alzheimer's diseases and amyotrophic lateral sclerosis. To obtain new ATP-competitive CK1δ inhibitors, three sets of benzimidazole-2-amino derivatives were synthesized ( 1 - 32 ), bearing different substituents on the fused benzo ring (R) and diverse pyrazole-containing acyl moieties on the 2-amino group. The best-performing derivatives were those featuring the (1H-pyrazol-3-yl)-acetyl moiety on the benzimidazol-2-amino scaffold ( 13 - 32 ), which showed CK1δ inhibitor activity in the low micromolar range. Among the R substituents, 5-cyano was the most advantageous, leading to a compound endowed with nanomolar potency ( 23 , IC 50 = 98.6 nM). Molecular docking and dynamics studies were performed to point out the inhibitor-kinase interactions.
Databáze: MEDLINE
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