Click-based synthesis of triazolobithiazole ΔF508-CFTR correctors for cystic fibrosis

Donald, Michael B.; Rodriguez, Kevin X.; Shay, Hannah; Phuan, Puay Wah; Kurth, Mark J.

doi:10.1016/j.bmc.2012.06.046

Cited by 15 publications

(11 citation statements)

References 12 publications

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“…As shown in Table 1, all the compounds were predicted to be endowed with high human intestinal absorption, being FCG (and 9d) characterized by better lipophilicity and logP values than corr4a, indicating that FCG could be proposed as lead compound for the multi-drug treatment of the basic defect underlying CF [51,52].…”

Section: In Silico Evaluation Of Adme Propertiesmentioning

confidence: 99%

NBD2 Is Required for the Rescue of Mutant F508del CFTR by a Thiazole-Based Molecule: A Class II Corrector for the Multi-Drug Therapy of Cystic Fibrosis

et al. 2021

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Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, an anion channel that regulates epithelial surface fluid secretion. The deletion of phenylalanine at position 508 (F508del) is the most common CFTR mutation. F508del CFTR is characterized by folding and trafficking defects, resulting in decreased functional expression of the protein on the plasma membrane. Several classes of small molecules, named correctors, have been developed to rescue defective F508del CFTR. Although individual correctors failed to improve the clinical status of CF patients carrying the F508del mutation, better results were obtained using correctors combinations. These results were obtained according to the premise that the administration of correctors having different sites of action should enhance F508del CFTR rescue. We investigated the putative site of action of an aminoarylthiazole 4-(3-chlorophenyl)-N-(3-(methylthio)phenyl)thiazol-2-amine, named FCG, with proven CFTR corrector activity, and its synergistic effect with the corrector VX809. We found that neither the total expression nor the maturation of WT CFTR transiently expressed in human embryonic kidney 293 cells was influenced by FCG, administrated alone or in combination with VX809. On the contrary, FCG was able to enhance F508del CFTR total expression, and its combination with VX809 provided a further effect, being able to increase not only the total expression but also the maturation of the mutant protein. Analyses on different CFTR domains and groups of domains, heterologously expressed in HEK293 cells, show that NBD2 is necessary for FCG corrector activity. Molecular modelling analyses suggest that FCG interacts with a putative region located into the NBD2, ascribing this molecule to class II correctors. Our study indicates that the continuous development and testing of combinations of correctors targeting different structural and functional defects of mutant CFTR is the best strategy to ensure a valuable therapeutic perspective to a larger cohort of CF patients.

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Section: In Silico Evaluation Of Adme Propertiesmentioning

confidence: 99%

NBD2 Is Required for the Rescue of Mutant F508del CFTR by a Thiazole-Based Molecule: A Class II Corrector for the Multi-Drug Therapy of Cystic Fibrosis

et al. 2021

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“…Thiourea 18 was condensed with 3-chloro-2,4-pentadione 19 in refluxing ethanol to afford 1-(2-amino-4-methylthiazol-5-yl)ethanone 20 in nearly quantitative yield, followed by bromination α to the carbonyl to give compound 21 . The subsequent condensation of intermediate 21 with 1-(3-acetylphenyl)thiourea 23 gave bithiazole 24 that was finally N-acetylated to obtain the desired compound 17 .…”

Section: Resultsmentioning

confidence: 99%

Discovery of Multitarget Agents Active as Broad-Spectrum Antivirals and Correctors of Cystic Fibrosis Transmembrane Conductance Regulator for Associated Pulmonary Diseases

et al. 2017

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Enteroviruses (EVs) are among the most frequent infectious agents in humans worldwide and represent the leading cause of upper respiratory tract infections. No drugs for the treatment of EV infections are currently available. Recent studies have also linked EV infection with pulmonary exacerbations, especially in cystic fibrosis (CF) patients, and the importance of this link is probably underestimated. The aim of this work was to develop a new class of multitarget agents active both as broad-spectrum antivirals and as correctors of the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) folding defect responsible for >90% of CF cases. We report herein the discovery of the first small molecules able to simultaneously act as correctors of the F508del-CFTR folding defect and as broad-spectrum antivirals against a panel of EVs representative of all major species.

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“…Likewise, 5‐arylidene‐2‐imino‐4‐thiazolidinones exhibit significant levels of anti‐inflammatory activity 4. Recently, Kurth and co‐workers have reported the synthesis of triazolobithiazole derivatives with cystic fibrosis corrector activity 5. Because of the wide spectrum of activity shown by the thiazole moiety, the design of amenable synthetic approaches to new and complex thiazole derivatives is still an attractive challenge and a focus of great interest.…”

Section: Introductionmentioning

confidence: 99%

5‐Alkenylthiazoles as In‐Out Dienes in Polar [4+2] Cycloaddition Reactions

et al. 2013

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5‐Alkenyl‐2‐aminothiazoles react as in‐out dienes with a wide range of electron‐poor dienophiles leading to the corresponding cycloaddition products in good to excellent yields. The [4+2] cycloadditions of 5‐alkenyl‐2‐aminothiazoles can be classified as site‐selective because only the diene moiety incorporating the formal C–C double bond of the heterocycle and that of the side‐chain is involved. Calculations of the HOMO energy values of representative 5‐alkenyl‐2‐aminothiazoles are disclosed. The cycloadditions are endo‐selective with N‐phenylmaleimide or maleic anhydride and regioselective when the reactions are conducted with nonsymmetrical dienophiles. Completely oxidized cycloadducts are obtained in the reactions of 5‐alkenyl‐2‐aminothiazoles with naphthoquinone or dimethyl acetylenedicarboxylate (DMAD). Unexpectedly, the reactions with 4‐phenyl‐1,2,4‐triazoline‐3,5‐dione (PTAD) are not stereospecific. A mechanism placed at the concerted/stepwise boundary is proposed.

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Click-based synthesis of triazolobithiazole ΔF508-CFTR correctors for cystic fibrosis

Cited by 15 publications

References 12 publications

NBD2 Is Required for the Rescue of Mutant F508del CFTR by a Thiazole-Based Molecule: A Class II Corrector for the Multi-Drug Therapy of Cystic Fibrosis

NBD2 Is Required for the Rescue of Mutant F508del CFTR by a Thiazole-Based Molecule: A Class II Corrector for the Multi-Drug Therapy of Cystic Fibrosis

Discovery of Multitarget Agents Active as Broad-Spectrum Antivirals and Correctors of Cystic Fibrosis Transmembrane Conductance Regulator for Associated Pulmonary Diseases

5‐Alkenylthiazoles as In‐Out Dienes in Polar [4+2] Cycloaddition Reactions

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