Design, synthesis, and biological testing of biphenylmethyloxazole inhibitors targeting HIV-1 reverse transcriptase.
Anti-HIV agents
Computer-aided drug design
Reverse transcriptase inhibitors
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
15 03 2023
15 03 2023
Historique:
received:
17
11
2022
revised:
20
02
2023
accepted:
27
02
2023
pmc-release:
15
03
2024
pubmed:
6
3
2023
medline:
21
3
2023
entrez:
5
3
2023
Statut:
ppublish
Résumé
We report non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) using a biphenylmethyloxazole pharmacophore. A crystal structure of benzyloxazole 1 was obtained and suggested the potential viability of biphenyl analogues. In particular, 6a, 6b, and 7 turned out to be potent NNRTIs with low-nanomolar activity in enzyme inhibition and infected T-cell assays, and with low cytotoxicity. Though modeling further suggested that analogues with fluorosulfate and epoxide warheads might provide covalent modification of Tyr188, synthesis and testing did not find evidence for this outcome.
Identifiants
pubmed: 36871704
pii: S0960-894X(23)00094-X
doi: 10.1016/j.bmcl.2023.129216
pmc: PMC10278203
mid: NIHMS1882221
pii:
doi:
Substances chimiques
reverse transcriptase, Human immunodeficiency virus 1
EC 2.7.7.-
Reverse Transcriptase Inhibitors
0
HIV Reverse Transcriptase
EC 2.7.7.49
Anti-HIV Agents
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
129216Subventions
Organisme : NIAID NIH HHS
ID : R01 AI155072
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM049551
Pays : United States
Informations de copyright
Copyright © 2023 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Références
Bioorg Med Chem Lett. 2006 Feb;16(3):663-7
pubmed: 16263277
Bioorg Chem. 2019 Aug;89:102974
pubmed: 31102693
ACS Med Chem Lett. 2021 Jan 06;12(2):249-255
pubmed: 33603971
J Med Chem. 2022 Mar 10;65(5):3729-3757
pubmed: 35175760
Eur J Med Chem. 2018 Feb 10;145:726-734
pubmed: 29353724
J Am Chem Soc. 2008 Jul 23;130(29):9492-9
pubmed: 18588301
Acc Chem Res. 2009 Jun 16;42(6):724-33
pubmed: 19317443
Bioeng Transl Med. 2021 Jun 26;7(1):e10237
pubmed: 35079625
Bioorg Med Chem. 2016 Oct 15;24(20):4768-4778
pubmed: 27485603
Nat Rev Drug Discov. 2022 Dec;21(12):881-898
pubmed: 36008483
Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):9725-9730
pubmed: 28827354
J Med Chem. 2011 Dec 22;54(24):8582-91
pubmed: 22081993
Viruses. 2014 Oct 24;6(10):4095-139
pubmed: 25341668
Annu Rev Pharmacol Toxicol. 2015;55:249-67
pubmed: 25149918
Eur J Med Chem. 2017 Sep 29;138:96-114
pubmed: 28651155
J Am Chem Soc. 2012 Dec 5;134(48):19501-3
pubmed: 23163887
Bioorg Med Chem Lett. 2013 Feb 15;23(4):1110-3
pubmed: 23298809
J Med Chem. 2019 May 23;62(10):4851-4883
pubmed: 30516990