Discovery of Novel, Orally Bioavailable β-Amino Acid Azaindole Inhibitors of Influenza PB2

Abstract

In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic β-amino acid inhibitors, highlighted by compound . Compound showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.

Mechanochemical enzymatic resolution ofN-benzylated-β3-amino esters

“…β-Amino acids are rather interesting molecules that frequently exhibit exceptional biological properties [ 1 – 3 ]; for instance, some of them are efficient inhibitors of several enzymes [ 4 – 5 ]. Furthermore, β-amino acid residues can be used to protect peptides and proteins against the activity of proteolytic enzymes [ 6 – 7 ], or are precursors of numerous active compounds such as β-lactams [ 8 – 9 ].…”

Investigation of Binding Affinity between Potential Antiviral Agents and PB2 Protein of Influenza A: Non-equilibrium Molecular Dynamics Simulation Approach

“…The 3D structures of the complexes were taken from Protein Data Bank with PDB ID: 5JUN (A_PB2-4) 55 , 5BUH (A_PB2-12) and 5F79 (A_PB2-16) 56 . The 2D structures of the inhibitors (4), (12) and (16) are shown in Figure 1 .…”

6‐Methyl‐7‐Aryl‐7‐Deazapurine Nucleosides as Anti‐Trypanosoma cruzi Agents: Structure‐Activity Relationship and in vivo Efficacy

“…Bromination at C3 was effected by NBS/DMF to yield substituted heterocyclic analogues 73-76. [41][42] Vorbrüggen glycosylation [27] afforded the desired analogues 77-80 after direct deprotection in saturated Table 6. Activity of 14 against T. cruzi (Y strain) bloodstream trypomastigotes and intracellular amastigotes in 2D primary cardiac cells.…”

“…. [41][42] 5-Chloro-1H-pyrrolo [2,3-b]pyridine (500 mg, 3.28 mmol) was dissolved in anhydrous DMF (10 mL, 3 mL/mmol of SM), and NBS (642 mg, 3.61 mmol, 1.1 eq.) was added.…”