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Synthesis and Structure-activity Relationship of Aminoarylthiazole Derivatives as Potential Potentiators of the Chloride Transport Defect in Cystic Fibrosis

Author(s):

Nara Liessi, Emanuela Pesce, Annalisa Salis, Gianluca Damonte, Bruno Tasso, Elena Cichero, Nicoletta Pedemonte and Enrico Millo*   Pages 1 - 12 ( 12 )

Abstract:


Background: Cystic fibrosis (CF) is the autosomal recessive disorder most common in Caucasian populations. It is caused by mutations in the cystic fibrosis transmembrane regulator protein (CFTR). CFTR is predominantly expressed at the apical plasma membranes of the epithelial cells lining several organs, and functions as a cAMP-regulated chloride/bicarbonate channel. To address the underlying causes of cystic fibrosis, two biomolecular activities are required, namely correctors to increase CFTR levels at the cell surface, and potentiators to allow the effective opening of the CFTR channel.

Objective: In our previous data we demonstrated that some aminoarylthiazoles (AATs) have peculiar activity acting as correctors and as potentiator-like molecules. Curiously, a compound called 1 has been shown to be markedly active as a potentiator. Now, we have further modified its scaffold at different portions, for the identification of molecules with improved potency and effectiveness on mutant CFTR.

Methods: Starting from this active compound we synthesized a small library trying to improve the activity as potentiators. To extrapolate the contribution of a particular structural portion to bioactivity, we selectively modified one portion at a time.

Results: Our study has provided a structure-activity relationship (SAR) on AATs and led to the identification of some compounds, with a particular ability to act as CFTR potentiators.

Conclusion: Two compounds 2 and 13 appear to be promising molecules and could be used for the future development of potentiators of the chloride transport defect in cystic fibrosis.

Keywords:

Amide, Thiazole, Benzhydryl, Piperidine, Antimicrobial activity, Cephalosporins, N-Alkylamides, Listeria monocytogenes, Pseudomonas aeruginosa, Mueller–Hinton, Cystic fibrosis, CFTR, modulators, potentiators, aminoarylthiazole, thioureas.

Affiliation:

University of Genoa, Experimental Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research (CEBR), Viale Benedetto XV 1, IRCCS Istituto Giannina Gaslini, Genova, UOC Genetica Medica, via G.Gaslini 5, University of Genoa, Center of Excellence for Biomedical Research (CEBR), Viale Benedetto XV 9, University of Genoa, Experimental Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research (CEBR), Viale Benedetto XV 1, University of Genoa, Department of Pharmacy, Section of Medicinal Chemistry, Viale Benedetto XV 3, University of Genoa, Department of Pharmacy, Section of Medicinal Chemistry, Viale Benedetto XV 3, IRCCS Istituto Giannina Gaslini, Genova, UOC Genetica Medica, via G.Gaslini 5, University of Genoa, Experimental Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research (CEBR), Viale Benedetto XV 1



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