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Synthesis and biological evaluation of benzodiazepines containing a pentafluorosulfanyl group

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posted on 2023-06-09, 23:28 authored by Arathy Jose, Raysa Khan, Martin Mortensen, Remi Legay, Simon J Coles, Graham J Tizzard, Barnaby GreenlandBarnaby Greenland, Trevor G Smart, Mark BagleyMark Bagley, John SpencerJohn Spencer
The widely used pentafluorosulfanyl group (SF5) was deployed as a bioisosteric replacement for a chloro-group in the benzodiazepine diazepam (Valium™). Reaction of 2-amino-5-pentafluorosulfanyl-benzophenone with chloroacetyl chloride followed by hexamethylenetetramine, in the presence of ammonia, led to 7-sulfurpentafluoro-5-phenyl-1H-benzo[1,4]diazepin-2(3H)-one (2c). The latter was able to undergo a Pd-catalysed ortho-arylation, demonstrating that these highly fluorinated benzodiazepines can be further modified to form more complicated scaffolds. The replacement of Cl by the SF5 group, led to a loss of potency for potentiating GABAA receptor activation, most likely because of a lost ligand interaction with His102 in the GABAA receptor a subunit. Dedicated to Professor Jonathan Williams, an inspirational and humble pioneer, a colleague and mentor in chemistry.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Tetrahedron

ISSN

0040-4020

Publisher

Elsevier

Volume

85

Page range

1-6

Article number

a132020

Department affiliated with

  • Chemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2021-03-29

First Open Access (FOA) Date

2022-02-21

First Compliant Deposit (FCD) Date

2021-03-29

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