Synthesis and biological evaluation of benzodiazepines containing a pentafluorosulfanyl group

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. a132020 1-6. ISSN 0040-4020

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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. Dedicated to Professor Jonathan Williams, an inspirational and humble pioneer, a colleague and mentor in chemistry.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 29 Mar 2021 07:15
Last Modified: 07 May 2021 07:02
URI: http://sro.sussex.ac.uk/id/eprint/98122

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