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Synthesis and biological evaluation of benzodiazepines containing a pentafluorosulfanyl group

Synthesis and biological evaluation of benzodiazepines containing a pentafluorosulfanyl group
Synthesis and biological evaluation of benzodiazepines containing a pentafluorosulfanyl group
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 α subunit.
0040-4020
Jose, Arathy
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Tareque, Raysa Khan
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Mortensen, Martin
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Legay, Remi
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Coles, Simon J.
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Tizzard, Graham J.
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Greenland, Barnaby W.
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Smart, Trevor G.
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Bagley, Mark C.
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Spencer, John
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Jose, Arathy
2fdea2c1-adfe-4cac-b286-98877e71e6d2
Tareque, Raysa Khan
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Mortensen, Martin
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Legay, Remi
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Coles, Simon J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Tizzard, Graham J.
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Greenland, Barnaby W.
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Smart, Trevor G.
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Bagley, Mark C.
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Spencer, John
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Jose, Arathy, Tareque, Raysa Khan, Mortensen, Martin, Legay, Remi, Coles, Simon J., Tizzard, Graham J., Greenland, Barnaby W., Smart, Trevor G., Bagley, Mark C. and Spencer, John (2021) Synthesis and biological evaluation of benzodiazepines containing a pentafluorosulfanyl group. Tetrahedron, [132020]. (doi:10.1016/j.tet.2021.132020).

Record type: Article

Abstract

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 α subunit.

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accepted Tet paper 150221 - Accepted Manuscript
Restricted to Repository staff only until 20 February 2023.
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Accepted/In Press date: 8 February 2021
e-pub ahead of print date: 20 February 2021

Identifiers

Local EPrints ID: 447764
URI: http://eprints.soton.ac.uk/id/eprint/447764
ISSN: 0040-4020
PURE UUID: c767b514-c9e5-4518-8d6b-cc3d0208f001
ORCID for Simon J. Coles: ORCID iD orcid.org/0000-0001-8414-9272
ORCID for Graham J. Tizzard: ORCID iD orcid.org/0000-0002-1577-5779

Catalogue record

Date deposited: 19 Mar 2021 17:33
Last modified: 20 Mar 2021 02:37

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Contributors

Author: Arathy Jose
Author: Raysa Khan Tareque
Author: Martin Mortensen
Author: Remi Legay
Author: Simon J. Coles ORCID iD
Author: Barnaby W. Greenland
Author: Trevor G. Smart
Author: Mark C. Bagley
Author: John Spencer

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