Hong BT, Cheng YE, Cheng TJ, Fang JM. Boronate, trifluoroborate, sulfone, sulfinate and sulfonate congeners of oseltamivir carboxylic acid: Synthesis and anti-influenza activity. Eur J Med Chem. 2018 Dec 13;163:710-721
Tamiflu readily undergoes endogenous hydrolysis to give oseltamivir carboxylic acid (OC) as the active anti-influenza agent to inhibit the viral neuraminidase (NA). GOC is derived from OC by replacing the 5-amino group with a guanidino group. In this study, OC and GOC congeners with the carboxylic acid bioisosteres of boronic acid, trifluoroborate, sulfone, sulfinic acid, sulfonic acid and sulfonate ester were first synthesized, starting with conversion of OC to a Barton ester, followed by halodecarboxylation to give the iodocyclohexene, which served as a pivotal intermediate for palladium-catalyzed coupling reactions with appropriate diboron and thiol reagents. The enzymatic and cell-based assays indicated that the GOC congeners consistently displayed better NA inhibition and anti-influenza activity than the corresponding OC congeners. The GOC sulfonic acid congener (7a) was the most potent anti-influenza agent, showing EC50?=?2.2?nM against the wild-type H1N1 virus, presumably because the sulfonic acid 7a was more lipophilic than GOC and exerted stronger interactions on the three arginine residues (R118, R292 and R371) in the NA active site. Although the trifluoroborates, sulfones and sulfonate esters did not have acidic proton, they still exhibited appreciable NA inhibitory activity, indicating that the polarized B-F and S→O bonds still made sufficient interactions with the tri-arginine motif.
See Also:
Latest articles in those days:
- Evolution of H7N9 highly pathogenic avian influenza virus in the context of vaccination 5 hours ago
- Cost-effectiveness of high-dose influenza vaccination in the Netherlands: Incorporating the impact on both respiratory and cardiovascular hospitalizations 5 hours ago
- First human case of avian influenza A (H10N3) in Southwest China [preprint] 2 days ago
- Molecular characterization of the whole genome of H9N2 avian influenza virus isolated from Egyptian poultry farms 2 days ago
- Genetic drift and purifying selection shape within-host influenza A virus populations during natural swine infections 2 days ago
[Go Top] [Close Window]