Influenza Neuraminidase Inhibitors Possessing a Novel Hydrophobic Interaction in the Enzyme Active Site:  Design, Synthesis, and Structural Analysis of Carbocyclic Sialic Acid Analogues with Potent Anti-Influenza Activity

Abstract

The design, synthesis, and in vitro evaluation of the novel carbocycles as transition-state-based inhibitors of influenza neuraminidase (NA) are described. The double bond position in the carbocyclic analogues plays an important role in NA inhibition as demonstrated by the antiviral activity of 8 (IC50 = 6.3 microM) vs 9 (IC50 > 200 microM). Structure-activity studies of a series of carbocyclic analogues 6a-i identified the 3-pentyloxy moiety as an apparent optimal group at the C3 position with an IC50 value of 1 nM for NA inhibition. The X-ray crystallographic structure of 6h bound to NA revealed the presence of a large hydrophobic pocket in the region corresponding to the glycerol subsite of sialic acid. The high antiviral potency observed for 6h appears to be attributed to a highly favorable hydrophobic interaction in this pocket. The practical synthesis of 6 starting from (-)-quinic acid is also described.

Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09‐related pneumonia: an individual participant data meta‐analysis

“…Based upon what is known about the mechanism of action of NAIs,29, 30 it is theoretically possible that treatment might be ineffective [tending to produce an odds ratio (OR) close to 1] but rather implausible that it would be genuinely harmful, producing an OR > 1 as we measured. Instead, we surmise that NAIs were often prescribed after the development of pneumonia or clinical deterioration; furthermore, patients with IRP were admitted to hospital a median of 4 days from symptom onset, compared to 2 days for those with no pneumonia.…”

Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study

“…Through binding in the conserved catalytic domain of the enzyme, these drugs can inhibit all types and subtypes of influenza neuraminidase, but to varying degrees 2. In recent years, the human influenza A viruses have developed complete resistance to an older class of drugs, the adamantanes, indicating the ability of these viruses to develop and subsequently maintain resistance to antivirals 3.…”

Existing Influenza Antivirals: Their Mechanisms of Action and Potential in the Face of Avian Influenza

“…They served as the lead compounds for the development of the neuraminidase inhibitors that were eventually marketed for the treatment (and prophylaxis) of infl uenza A and B virus infections: zanamivir (Relenza ® , 4 -guanidino -Neu5Ac2en, GG167) 36 and oseltamivir (Tamifl u ® , GS4071 ethyl ester, GS4104, Ro64 -0796) 37 ( Fig. 1.8 ).…”

“…Locations of oseltamivir -resistance mutations (i.e., H274Y) showing that the tyrosine at position 252 is involved in a network of hydrogen bonds in group -1 (H5N1 and H1N1) neuraminidases. 44 (Figure 1.9A was taken from Kim et al 37 and De Clercq, 43 and Fig. 1.9B was taken from Russell et al 44 ) See color insert.…”