Δf508-CFTR correctors: Synthesis and evaluation of thiazole-tethered imidazolones, oxazoles, oxadiazoles, and thiadiazoles

Long Ye, Bao Hu, Faris El-Badri, Brandi M. Hudson, Puay Wah Phuan, A. S. Verkman, Dean J. Tantillo, Mark J. Kurth

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The most common mutation causing cystic fibrosis (CF) is deletion of phenylalanine residue 508 in the cystic fibrosis transmembrane regulator conductance (CFTR) protein. Small molecules that are able to correct the misfolding of defective ΔF508-CFTR have considerable promise for therapy. Reported here are the design, preparation, and evaluation of five more hydrophilic bisazole analogs of previously identified bithiazole CF corrector 1. Interestingly, bisazole ΔF508-CFTR corrector activity was not increased by incorporation of more H-bond acceptors (O or N), but correlated best with the overall bisazole molecular geometry. The structure activity data, together with molecular modeling, suggested that active bisazole correctors adopt a U-shaped conformation, and that corrector activity depends on the molecule's ability to access this molecular geometry.

Original languageEnglish (US)
Pages (from-to)5840-5844
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2014

Fingerprint

Oxazoles
Thiadiazoles
Oxadiazoles
Thiazoles
Cystic Fibrosis Transmembrane Conductance Regulator
Cystic Fibrosis
Molecules
Molecular modeling
Geometry
Phenylalanine
Conformations
Mutation
imidazolone
Proteins
Therapeutics

Keywords

  • C,C-linked bisazoles
  • Correctors
  • Cystic fibrosis
  • Transmembrane regulator

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Δf508-CFTR correctors : Synthesis and evaluation of thiazole-tethered imidazolones, oxazoles, oxadiazoles, and thiadiazoles. / Ye, Long; Hu, Bao; El-Badri, Faris; Hudson, Brandi M.; Phuan, Puay Wah; Verkman, A. S.; Tantillo, Dean J.; Kurth, Mark J.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 24, No. 24, 15.12.2014, p. 5840-5844.

Research output: Contribution to journalArticle

Ye, Long ; Hu, Bao ; El-Badri, Faris ; Hudson, Brandi M. ; Phuan, Puay Wah ; Verkman, A. S. ; Tantillo, Dean J. ; Kurth, Mark J. / Δf508-CFTR correctors : Synthesis and evaluation of thiazole-tethered imidazolones, oxazoles, oxadiazoles, and thiadiazoles. In: Bioorganic and Medicinal Chemistry Letters. 2014 ; Vol. 24, No. 24. pp. 5840-5844.
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abstract = "The most common mutation causing cystic fibrosis (CF) is deletion of phenylalanine residue 508 in the cystic fibrosis transmembrane regulator conductance (CFTR) protein. Small molecules that are able to correct the misfolding of defective ΔF508-CFTR have considerable promise for therapy. Reported here are the design, preparation, and evaluation of five more hydrophilic bisazole analogs of previously identified bithiazole CF corrector 1. Interestingly, bisazole ΔF508-CFTR corrector activity was not increased by incorporation of more H-bond acceptors (O or N), but correlated best with the overall bisazole molecular geometry. The structure activity data, together with molecular modeling, suggested that active bisazole correctors adopt a U-shaped conformation, and that corrector activity depends on the molecule's ability to access this molecular geometry.",
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