Discovery of Novel Boron-Containing N-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-Resistant

Abstract

To address drug resistance to influenza virus neuraminidase inhibitors (NAIs), a series of novel boron-containing N-substituted oseltamivir derivatives were designed and synthesized to target the 150-cavity of neuraminidase (NA). In NA inhibitory assays, it was found that most of the new compounds exhibited moderate inhibitory potency against the wild-type NAs. Among them, compound 2c bearing 4-(3-boronic acid benzyloxy)benzyl group displayed weaker or slightly improved activities against group-1 NAs (H1N1, H5N1, H5N8 and H5N1-H274Y) compared to that of oseltamivir carboxylate (OSC). Encouragingly, 2c showed 4.6 times greater activity than OSC toward H5N1-H274Y NA. Moreover, 2c exerted equivalent or more potent antiviral activities than OSC against H1N1, H5N1 and H5N8. Additionally, 2c demonstrated low cytotoxicity in vitro and no acute toxicity at the dose of 1000 mg/kg in mice. Molecular docking of 2c was employed to provide a possible explanation for the improved anti-H274Y NA activity, which may be due to the formation of key additional hydrogen bonds with surrounding amino acid residues, such as Arg152, Gln136 and Val149. Taken together, 2c appeared to be a promising lead compound for further optimization.

Chemoselective Reactions of Functionalized Sulfonyl Halides

“…[167] Other examples include CrO 3 -mediated oxidation of aromatic side chains, [22] MnO 2 -promoted dehydrogenative oxidation of β-aminoethane sulfonyl fluorides to corresponding ethylene derivatives, [168] Upjohn dihydroxylation, [169] sulfide to sulfoxide oxidation with NaIO 4 , [64] and alkylationoxidation sequence. [170] The SO 2 F fragment is also tolerant to various reductive agents, including NaBH 3 CN, [171] NaBH(OAc) 3 , [24,25,57] diphenyl disiloxane, [172] B 2 H 6 and borane complexes, [89,166,173] DIBAL, [57] sodium ditionite, [174] Bu 3 SnH, [175] Zn -HCl,, [176] Zn -HOAc, [157] Fe -HCl, [177] and Pd- [21,25,59,67,76,[177][178][179] or Ni- [180] catalyzed hydrogenation (Scheme 22).…”

“…The SO 2 F fragment is also tolerant to various reductive agents, including NaBH 3 CN, [171] NaBH(OAc) 3 , [24,25,57] diphenyl disiloxane, [172] B 2 H 6 and borane complexes, [89,166,173] DIBAL, [57] sodium ditionite, [174] Bu 3 SnH, [175] Zn – HCl,, [176] Zn – HOAc, [157] Fe – HCl, [177] and Pd‐ [21,25,59,67,76,177–179] or Ni‐ [180] catalyzed hydrogenation (Scheme 22).…”

Recent advances of phenotypic screening strategies in the application of anti-influenza virus drug discovery

“…2) mainly include M2 ion channel blockers: amantadine (1) and rimantadine (2), NA inhibitors: zanamivir (3), oseltamivir phosphate (4), peramivir (5) and laninamivir octanoate (6), and a PA inhibitor: baloxavir marboxil (7). [20][21][22] In the early stage, the existing antivirals have achieved remarkable results in the prevention and treatment of influenza. However, due to the highly error-prone properties of viral RdRp, drug-resistant viruses with reduced drug sensitivity emerge consistently, and their ability of human-tohuman transmission threatens again public health.…”

“…Molecular mechanism studies have found that 3061 (21) targeted the influenza NP with an IC 50 value of 0.1 μmol L −1 against reconstituted RdRp but led to resistance with the Y52H mutation on the NP (IC 50 > 30 μmol L −1 ). In addition, they found another compound, 367 (22), targeting PB1, which showed an inhibitory effect on RdRp enzymatic activity (IC 50 = 0.3-1 μmol L −1 ), and the mutant recombinant virus with H456P substitution in PB1 as well as the corresponding mutant protein expressed in the cell-based viral polymerase assay system had elevated resistance to 22 (IC 50 > 100 μmol L −1 ). In summary, the screening yielded two distinct classes of influenza virus inhibitors, thereby establishing a solid groundwork for the development of novel anti-influenza drugs.…”

“…2) mainly include M2 ion channel blockers: amantadine ( 1 ) and rimantadine ( 2 ), NA inhibitors: zanamivir ( 3 ), oseltamivir phosphate ( 4 ), peramivir ( 5 ) and laninamivir octanoate ( 6 ), and a PA inhibitor: baloxavir marboxil ( 7 ). 20–22…”