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Difluoromethylbenzoxazole Pyrimidine Thioether Derivatives: A Novel Class of Potent Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

Boyer, Jeremie; Arnoult, Eric; Medebielle, Maurice; Guillemont, Jerome; Unge, Johan LU and Jochmans, Dirk (2011) In Journal of Medicinal Chemistry 54(23). p.7974-7985
Abstract
This paper reports the synthesis and antiviral properties of new difluoromethylbenzoxazole (DFMB) pyrimidine thioether derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors. By use of a combination of structural biology study and traditional medicinal chemistry, several members of this novel class were synthesized using a single electron transfer chain process (radical nucleophilic substitution, Si) and were found to be potent against wild-type HIV-1 reverse transcriptase, with low cytotoxicity but with moderate activity against drug-resistant strains. The most promising compound 2,4 showed a significant EC(50) value close to 6.4 nM against HIV-1 IIIB, a moderate EC(50) value close to 54 mu M against an NNRTI resistant... (More)
This paper reports the synthesis and antiviral properties of new difluoromethylbenzoxazole (DFMB) pyrimidine thioether derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors. By use of a combination of structural biology study and traditional medicinal chemistry, several members of this novel class were synthesized using a single electron transfer chain process (radical nucleophilic substitution, Si) and were found to be potent against wild-type HIV-1 reverse transcriptase, with low cytotoxicity but with moderate activity against drug-resistant strains. The most promising compound 2,4 showed a significant EC(50) value close to 6.4 nM against HIV-1 IIIB, a moderate EC(50) value close to 54 mu M against an NNRTI resistant double mutant (K103N + Y181C), but an excellent selectivity index >15477 (CC(50) > 100 mu M). (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
54
issue
23
pages
7974 - 7985
publisher
American Chemical Society (ACS)
external identifiers
  • wos:000297445400003
  • scopus:82555187418
ISSN
1520-4804
DOI
10.1021/jm200766b
language
English
LU publication?
yes
id
8f9705d0-97f0-43e8-964a-a7c3facd2985 (old id 2320759)
date added to LUP
2012-01-31 09:34:03
date last changed
2017-11-12 03:03:21
@article{8f9705d0-97f0-43e8-964a-a7c3facd2985,
  abstract     = {This paper reports the synthesis and antiviral properties of new difluoromethylbenzoxazole (DFMB) pyrimidine thioether derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors. By use of a combination of structural biology study and traditional medicinal chemistry, several members of this novel class were synthesized using a single electron transfer chain process (radical nucleophilic substitution, Si) and were found to be potent against wild-type HIV-1 reverse transcriptase, with low cytotoxicity but with moderate activity against drug-resistant strains. The most promising compound 2,4 showed a significant EC(50) value close to 6.4 nM against HIV-1 IIIB, a moderate EC(50) value close to 54 mu M against an NNRTI resistant double mutant (K103N + Y181C), but an excellent selectivity index >15477 (CC(50) > 100 mu M).},
  author       = {Boyer, Jeremie and Arnoult, Eric and Medebielle, Maurice and Guillemont, Jerome and Unge, Johan and Jochmans, Dirk},
  issn         = {1520-4804},
  language     = {eng},
  number       = {23},
  pages        = {7974--7985},
  publisher    = {American Chemical Society (ACS)},
  series       = {Journal of Medicinal Chemistry},
  title        = {Difluoromethylbenzoxazole Pyrimidine Thioether Derivatives: A Novel Class of Potent Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors},
  url          = {http://dx.doi.org/10.1021/jm200766b},
  volume       = {54},
  year         = {2011},
}