Discovery of a novel highly potent broad-spectrum heterocyclic chemical series of arenavirus cell entry inhibitors.
Arenavirus
Entry inhibitor
Junin
Lassa
Machupo
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:
01 06 2021
01 06 2021
Historique:
received:
23
12
2020
revised:
12
03
2021
accepted:
14
03
2021
entrez:
9
5
2021
pubmed:
10
5
2021
medline:
18
9
2021
Statut:
ppublish
Résumé
We identified and explored the structure-activity relationship (SAR) of a novel heterocyclic chemical series of arenavirus cell entry inhibitors. Optimized lead compounds, including diphenyl-substituted imidazo[1,2-a]pyridines, benzimidazoles, and benzotriazoles exhibited low to sub-nanomolar potency against both pseudotyped and infectious Old and New World arenaviruses, attractive metabolic stability in human and most nonhuman liver microsomes as well as a lack of hERG K + channel or CYP enzyme inhibition. Moreover, the straightforward synthesis of several lead compounds (e.g., the simple high yield 3-step synthesis of imidazo[1,2-a]pyridine 37) could provide a cost-effective broad-spectrum arenavirus therapeutic that may help to minimize the cost-prohibitive burdens associated with treatments for emerging viruses in economically challenged geographical settings.
Identifiants
pubmed: 33965007
pii: S0960-894X(21)00209-2
doi: 10.1016/j.bmcl.2021.127983
pmc: PMC10187606
mid: NIHMS1746546
pii:
doi:
Substances chimiques
Antiviral Agents
0
Heterocyclic Compounds
0
Viral Envelope Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
127983Subventions
Organisme : NIAID NIH HHS
ID : R43 AI112097
Pays : United States
Organisme : NIAID NIH HHS
ID : R44 AI112097
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.
Références
Antivir Ther. 2005;10(7):841-7
pubmed: 16312180
J Natl Med Assoc. 2010 Dec;102(12):1243-6
pubmed: 21287906
Viruses. 2012 Jan;4(1):83-101
pubmed: 22355453
Nat Med. 2004 Dec;10(12 Suppl):S110-21
pubmed: 15577929
Bioorg Med Chem Lett. 2019 Nov 15;29(22):126620
pubmed: 31537423
JAMA. 1990 Oct 24-31;264(16):2093-6
pubmed: 2214077
J Gastroenterol Hepatol. 2004 Nov;19(11):1312-7
pubmed: 15482540
Int J Infect Dis. 2019 Oct;87:15-20
pubmed: 31357056
J Virol. 2011 Oct;85(19):10404-8
pubmed: 21795336
Antiviral Res. 2008 Apr;78(1):103-15
pubmed: 18241935
Infect Genet Evol. 2009 Jul;9(4):417-29
pubmed: 19460307
Eur Arch Otorhinolaryngol. 2011 Feb;268(2):197-201
pubmed: 20809263
N Engl J Med. 1986 Jan 2;314(1):20-6
pubmed: 3940312
J Vector Borne Dis. 2007 Mar;44(1):1-11
pubmed: 17378212
Bioorg Med Chem Lett. 2013 Feb 1;23(3):744-9
pubmed: 23265895
Clin Infect Dis. 2001 Nov 15;33(10):1707-12
pubmed: 11595975
Emerg Infect Dis. 2006 May;12(5):835-7
pubmed: 16704848
PLoS Pathog. 2018 Dec 21;14(12):e1007439
pubmed: 30576397
J Biol Chem. 2011 Feb 25;286(8):6192-200
pubmed: 21159779
J Virol. 2008 Nov;82(21):10768-75
pubmed: 18715909
Curr Top Microbiol Immunol. 2002;262:75-109
pubmed: 11987809
Bioorg Med Chem Lett. 2013 Feb 1;23(3):750-6
pubmed: 23265900
Curr Opin Virol. 2019 Feb;34:18-28
pubmed: 30497052
PLoS Negl Trop Dis. 2009;3(3):e388
pubmed: 19255625
Virus Res. 2009 Mar;140(1-2):24-31
pubmed: 19041349