hERG optimizations of IMB1603, discovery of alternative benzothiazinones as new antitubercular agents.
Antitubercular agents
Benzothiazinones
Structure-activity relationships
hERG
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
01 Oct 2019
01 Oct 2019
Historique:
received:
15
04
2019
revised:
23
05
2019
accepted:
18
06
2019
pubmed:
30
6
2019
medline:
5
11
2019
entrez:
30
6
2019
Statut:
ppublish
Résumé
IMB1603, a new benzothiazinone lead discovered by our lab, exhibited potent anti-MTB activity in vitro and in vivo, but significant hERG binding potency (IR > 90% at 10 μM). Thus, we embarked on a lead optimization program with the goal of identifying alternative leads that could reduce the hERG liability without sacrificing antimycobacterial potency. Compounds 2c and 4c were identified to maintain the anti-MTB activity (MICs <0.035-0.078 μM), and had lower hERG binding affinity (IR < 50% at 10 μM). Both of them were also found to have acceptable safety and pharmacokinetic properties. Studies to determine the in vivo efficacy of 2c and 4c are currently underway.
Identifiants
pubmed: 31254922
pii: S0223-5234(19)30580-X
doi: 10.1016/j.ejmech.2019.06.053
pii:
doi:
Substances chimiques
Antitubercular Agents
0
Benzothiazoles
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
208-217Informations de copyright
Copyright © 2019 Elsevier Masson SAS. All rights reserved.