Development of novel S-N3-DABO derivatives as potent non-nucleoside reverse transcriptase inhibitors with improved potency and selectivity.
Eur J Med Chem
; 247: 115042, 2023 Feb 05.
Article
de En
| MEDLINE
| ID: mdl-36577220
ABSTRACT
Following on our initial discovery of S-CN-DABOs as non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel S-N3-DABO derivatives F1-F31 were developed by substituting the cyano group of S-CN-DABOs with azide group. Some of these compounds were conferred significantly increased potency against wild-type HIV-1 and clinically observed mutant strains. Remarkably, the best compound F10 exerted a 7-fold improvement in potency (EC50 = 0.053 µM) and 12.5-fold higher selectivity (SI = 6818) in MT-4 cells infected with wild-type HIV-1, compared to that of the parent compound B1 (EC50 = 370 nM, SI = 547). The anti-HIV-1 activity of F10 against the tested mutant strains was prominently enhanced. For wild-type reverse transcriptase, it was approximately 19-fold more potent (IC50 = 0.080 µM) than B1 (IC50 = 1.51 µM). It was not found that this analog had significant inhibition of hERG, CYP, and acute toxicity after a single dose of F10 (1.0 g/kg).
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
VIH-1 (Virus de l'Immunodéficience Humaine de type 1)
/
Agents antiVIH
Langue:
En
Journal:
Eur J Med Chem
Année:
2023
Type de document:
Article