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 (SF
5) 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 SF
5 group, led to a loss of potency for potentiating GABA
A receptor activation, most likely because of a lost ligand interaction with His102 in the GABA
A receptor α subunit. Dedicated to Professor Jonathan Williams, an inspirational and humble pioneer, a colleague and mentor in chemistry.
Benzodiazepines, Bioisosteres, Electrophysiology, GABA, HEK cells, Medicinal chemistry
Jose, Arathy
2fdea2c1-adfe-4cac-b286-98877e71e6d2
Tareque, Raysa Khan
f78b375e-753f-4634-8713-4453ad308401
Mortensen, Martin
3d712f8f-c0bc-4607-aede-829debbfd559
Legay, Remi
f2ae9412-2d2e-4d49-8c18-d95d522dd980
Coles, Simon J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Greenland, Barnaby W.
fd91bfa7-8217-4006-bdfa-e1d0f6cc84f1
Smart, Trevor G.
f0cfc3e5-a987-4563-bc8c-8d10465f5aa7
Bagley, Mark C.
2261d598-e7c0-445e-b6e1-d1a99f2bde7c
Spencer, John
a3cf55cd-a4c7-4af6-b16c-96c8fb8c4cf4
9 April 2021
Jose, Arathy
2fdea2c1-adfe-4cac-b286-98877e71e6d2
Tareque, Raysa Khan
f78b375e-753f-4634-8713-4453ad308401
Mortensen, Martin
3d712f8f-c0bc-4607-aede-829debbfd559
Legay, Remi
f2ae9412-2d2e-4d49-8c18-d95d522dd980
Coles, Simon J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Greenland, Barnaby W.
fd91bfa7-8217-4006-bdfa-e1d0f6cc84f1
Smart, Trevor G.
f0cfc3e5-a987-4563-bc8c-8d10465f5aa7
Bagley, Mark C.
2261d598-e7c0-445e-b6e1-d1a99f2bde7c
Spencer, John
a3cf55cd-a4c7-4af6-b16c-96c8fb8c4cf4
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, 85, [132020].
(doi:10.1016/j.tet.2021.132020).
Abstract
The widely used pentafluorosulfanyl group (SF
5) 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 SF
5 group, led to a loss of potency for potentiating GABA
A receptor activation, most likely because of a lost ligand interaction with His102 in the GABA
A receptor α subunit. Dedicated to Professor Jonathan Williams, an inspirational and humble pioneer, a colleague and mentor in chemistry.
Text
accepted Tet paper 150221
- Accepted Manuscript
More information
Accepted/In Press date: 8 February 2021
e-pub ahead of print date: 20 February 2021
Published date: 9 April 2021
Additional Information:
Funding Information:
The authors acknowledge financial support from the ERDF (LabFact: InterReg V project 121). We thank Dr Alaa Abdul-Sada for HRMS measurements.
Publisher Copyright:
© 2021 Elsevier Ltd
Keywords:
Benzodiazepines, Bioisosteres, Electrophysiology, GABA, HEK cells, Medicinal chemistry
Identifiers
Local EPrints ID: 447764
URI: http://eprints.soton.ac.uk/id/eprint/447764
ISSN: 0040-4020
PURE UUID: c767b514-c9e5-4518-8d6b-cc3d0208f001
Catalogue record
Date deposited: 19 Mar 2021 17:33
Last modified: 17 Mar 2024 06:25
Export record
Altmetrics
Contributors
Author:
Arathy Jose
Author:
Raysa Khan Tareque
Author:
Martin Mortensen
Author:
Remi Legay
Author:
Barnaby W. Greenland
Author:
Trevor G. Smart
Author:
Mark C. Bagley
Author:
John Spencer
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics
