Discovery of novel polyheterocyclic neuraminidase inhibitors with 1,3,4-oxadiazole thioetheramide as core backbone

Eur J Med Chem. 2024 Mar 12;269:116305. doi: 10.1016/j.ejmech.2024.116305. Online ahead of print.ABSTRACTInspired by our earlier findings regarding neuraminidase (NA) inhibitors interacting with 150-cavity or 430-cavity of NA, sixteen novel polyheterocyclic NA inhibitors with 1,3,4-oxadiazole thioetheramide as core backbone were designed and synthesized based on the lead compound ZINC13401480. Of the synthesized compounds, compound N5 targeting 150-cavity exerts the best inhibitory activity against the wild-type H5N1 NA, with IC50 value of 0.14 μM, which is superior to oseltamivir carboxylate (OSC) (IC50 = 0.31 μM). Compound N10 targeting 430-cavity exhibits the best activity against the H5N1-H274Y mutant NA. Although the activity of N10 is comparable to that of OSC for wild-type H5N1 inhibition, it is approximately 60-fold more potent than OSC against the H274Y mutant, suggesting that it is not easy for the virus to develop drug resistance and is attractive for drug development. N10 (EC50 = 0.11 μM) also exhibits excellent antiviral activity against H5N1, which is superior to the positive control OSC (EC50 = 1.47 μM). Molecular docking study shows that the occupation of aromatic fused rings and oxadiazole moiety at the active site and the extension of the substituted phenyl to the 150-cavity or 430-cavity make great contributions to the good potency of this series of polyheterocyclic NA inhibitors. Some advancements in the discovery of effective target-specific NA inhibi...
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Source Type: research