Jose, A;
Tareque, RK;
Mortensen, M;
Legay, R;
Coles, SJ;
Tizzard, GJ;
Greenland, BW;
... Spencer, J; + view all
(2021)
Synthesis and biological evaluation of benzodiazepines containing a pentafluorosulfanyl group.
Tetrahedron
, 85
, Article 132020. 10.1016/j.tet.2021.132020.
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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.
| Type: | Article |
|---|---|
| Title: | Synthesis and biological evaluation of benzodiazepines containing a pentafluorosulfanyl group |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.tet.2021.132020 |
| Publisher version: | https://doi.org/10.1016/j.tet.2021.132020 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | benzodiazepines Medicinal chemistry, GABA, Bioisosteres, Electrophysiology, HEK cells |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10129789 |
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