367252-68-4

Upstream product

• 24424-99-5 di-tert-butyl dicarbonate 
• 196618-13-0 oseltamivir 
• 891862-23-0 ethyl (1S,5S,6R)-7-acetyl-5-(tert-butoxycarbonylamino)-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate 
• 584-02-1 2-pentanol 
• 1012814-35-5 (3R,4R,5S)-ethyl 4-amino-5-(tert-butoxycarbonylamino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate 
• 108-24-7 acetic anhydride 
• 204255-11-8 oseltamivir phosphate 
• 64-17-5 ethanol 
• 1062100-85-9 4-acetamido-5-(tert-butoxycarbonyl)amino-3-(1-ethylpropoxy)-1-iodo-1-cyclohexene 
• 201230-82-2 carbon monoxide 
• 1809-05-8 3-pentyl iodide 
• 1137726-89-6 ethyl (3R,4R,5S)-4-acetylamino-5-tert-butoxycarbonylamino-3-hydroxy-cyclohex-1-enecarboxylate 
• 367252-67-3 (3R,4R,5S)-4-azido-5-tert-butoxycarbonylamino-3-(1-ethylpropoxy)cyclohex-1-enecarboxylic acid ethyl ester 
• 507-09-5 tiolacetic acid 

Downstream Products

• 204255-11-8 oseltamivir phosphate 
• 196618-13-0 oseltamivir 
• 1448675-34-0 (3R,4R,5S)-ethyl 4-acetamido-5-[(tert-butoxycarbonyl)amino]-3-(pentan-3-yloxy)-2-[2-(triethoxysilyl)ethyl]cyclohex-1-enecarboxylate 
• 764639-63-6 (3R,4R,5S)-4-acetamido-5-[(tert-butoxycarbonyl)-amino]-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid 
• 1122748-00-8 C₁₅H₂₉N₂O₅P 
• 1158845-41-0 C₁₉H₃₇N₂O₅P 
• 1122748-01-9 C₁₆H₃₁N₄O₅P 
• 1401808-94-3 C₁₈H₃₅N₄O₅P 
• 1062100-85-9 4-acetamido-5-(tert-butoxycarbonyl)amino-3-(1-ethylpropoxy)-1-iodo-1-cyclohexene 
• 1616373-90-0 dibutyl (3R,4R,5S)-4-acetamido-5-tert-butoxycarbonylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-phosphonate 
• 1616373-91-1 C₃₀H₅₇N₂O₇P 
• 1616373-92-2 di(3-phenylprop-1-yl) (3R,4R,5S)-4-acetamido-5-tert-butoxycarbonylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-phosphonate 
• 1616373-93-3 di[3-(1H-indol-3-yl)propyl] (3R,4R,5S)-4-acetamido-5-tert-butoxycarbonylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-phosphonate 
• 1616373-94-4 dibutyl (3R,4R,5S)-4-acetamido-5-[N²,N³-bis(tert-butoxycarbonyl)guanidino]-3-(1-ethylpropoxy)-1-cyclohexene-1-phosphonate 

Relevant academic research and scientific papers

Design, synthesis, and evaluation of carboxyl-modified oseltamivir derivatives with improved lipophilicity as neuraminidase inhibitors

In this study, a series of carboxyl-modified oseltamivir analogs with improved lipophilicity were designed and synthesized, and their inhibitory activities against neuraminidase from influenza A virus H5N1 subtype were evaluated. The results demonstrated that compound 5m exhibited potent inhibitory activity (IC50 = 1.30 ± 0.23 μM), and it targeted the recently discovered 430-cavity. Compound 5m (Log D = ?0.12) is more lipophilic than oseltamivir carboxylate (Log D = ?1.69) at pH 7.4, which is potentially propitious to improved membrane permeability and oral drug absorption. Meanwhile, 5m showed high stability in human liver microsomes. The findings of this study can be valuable in identifying neuraminidase inhibitors with optimal lipophilicity and in the exploration of 430-cavity.

Discovery of novel 1,2,3-triazole oseltamivir derivatives as potent influenza neuraminidase inhibitors targeting the 430-cavity

A novel series of 1,2,3-triazole oseltamivir derivatives, which could simultaneously occupy the classical NA catalytic site and the newly reported 430-cavity, were designed, synthesized, and evaluated for their anti-influenza activities. The results demonstrated that four compounds (6g, 6l, 6y and 8c) showed robust anti-influenza potencies against H5N1, H5N2 and H5N6 strains in both enzymatic assay and cellular assay. Especially, 6l was proved to possess the most potent and broad-spectrum anti-influenza activity, with IC50 values of 0.12 μM, 0.049 μM and 0.16 μM and EC50 values of 2.45 μM, 0.43 μM and 2.8 μM against H5N1, H5N2 and H5N6 strains, respectively, which were slightly weaker than oseltamivir carboxylate. In addition, in the embryonated egg model, 6l achieved the similar protective effect against H9N2 strain with oseltamivir carboxylate in the tested concentrations. Preliminary structure-activity relationships (SARs), molecular modeling, and calculated physicochemical properties of selected compounds were also discussed.

Discovery of C-1 modified oseltamivir derivatives as potent influenza neuraminidase inhibitors

Inspired by our initial discovery about a series of neuraminidase (NA) inhibitors targeting the 150-cavity, in present study, we designed, synthesized, and biologically tested a panel of novel oseltamivir derivatives with C-1 modification, targeting the 430-cavity, an additional binding site which widely and stably existed in both group-1 and group-2 NAs. Some of the synthesized compounds displayed robust anti-influenza potencies against H5N1 and H5N6 viruses. Among them, compound 8b exerted the greatest inhibition, with IC50 values of 0.088 and 0.097 μM and EC50 values of 4.26 and 1.31 μM against H5N1 and H5N6 strains, respectively, which are similar to those of oseltamivir carboxylate (OSC). And its potency against mutant H5N1-H274Y NA was just 7-fold weaker than OSC. Molecular modeling revealed the elongated group at C-1 position being projected toward the 430-cavity. Notably, although compound 8b was not sensitive toward H5N1 strain relative to OSC in the embryonated egg model, it displayed greater anti-influenza virus effect against H5N6 strain than OSC at the concentration of 10 mmol/L. Overall, this work provided unique insights in the discovery of potent inhibitors against both group-1 and group-2 NAs.

Divalent oseltamivir analogues as potent influenza neuraminidase inhibitors

A panel of divalent oseltamivir and guanidino oseltamivir analogues with esterification on the carboxyl acid group as potent inhibitors of influenza virus neuraminidase was prepared via click reaction. The primary structure activity relationship study demonstrated that appropriate distance between two oseltamivir monomers around 30 ? can crosslink two adjacent neuraminidase tetramers on the virion surface and result in highly effective NA inhibitors against three strains of influenza virus and H7N9 virus like particle. This strategy also provides a basis for the multivalent modification on oseltamivir.

A dual-functional molecular strategy for in situ suppressing and visualizing of neuraminidase in aqueous solution using iridium(III) complexes

We have designed for the first time a dual-functional luminescent probe and inhibitor of neuraminidase (NA), a key influenza target. The lead iridium(iii) complex exhibited enhanced inhibition against NA compared to the FDA-approved antiviral drug, oseltamivir, and could detect NA even in the presence of an autofluorescent background.

Novel anti-influenza virus oseltamivir derivative as well as preparation method and application thereof

The invention belongs to the field of medicinal chemistry and chemical synthesis, and particularly relates to an oseltamivir derivative and a preparation method and application thereof, and the oseltamivir derivative has a structure as shown in a general

Design, synthesis and biological evaluation of “Multi-Site”-binding influenza virus neuraminidase inhibitors

Encouraged by our earlier discovery of neuraminidase inhibitors targeting 150-cavity or 430-cavity, herein, to yield more potent inhibitors, we designed, synthesized, and biologically evaluated a series of novel oseltamivir derivatives via modification of C-1 and C5–NH2 of oseltamivir by exploiting 150-cavity and/or 430-cavity. Among the synthesized compounds, compound 15e, the most potent N1-selective inhibitor targeting 150-cavity, showed 1.5 and 1.8 times greater activity than oseltamivir carboxylate (OSC) against N1 (H5N1) and N1 (H5N1–H274Y). In cellular assays, 15e also exhibited greater potency than OSC against H5N1 with EC50 of 0.66 μM. In addition, 15e demonstrated low cytotoxicity in vitro and low acute toxicity in mice. Molecular docking studies provided insights into the high potency of 15e against N1 and N1–H274Y mutant NA. Overall, we envisioned that the significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors may lead to further investigation of more potent anti-influenza agents.

Boronate, trifluoroborate, sulfone, sulfinate and sulfonate congeners of oseltamivir carboxylic acid: Synthesis and anti-influenza activity

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.

Expedient synthesis of oseltamivir and related compounds via direct olefin diazidation-diamidation reaction

Disclosed herein are improved methods for the preparation of oseltamivir, and intermediates useful thereto.

Acylguanidine derivatives of zanamivir and oseltamivir: Potential orally available prodrugs against influenza viruses

Zanamivir (ZA) and guanidino-oseltamivir carboxylic acid (GOC) are very potent inhibitors against influenza neuraminidase (NA). The guanidinium moiety plays an important role in NA binding; however, its polar cationic nature also hinders the use of ZA and GOC from oral administration. In this study, we investigated the use of ZA and GOC acylguanidine derivatives as possible orally available prodrugs. The acylguanidine derivatives were prepared by coupling with either n-octanoic acid or (S)-naproxen. The lipophilic acyl substituents were verified to improve cell permeability, and may also improve the bioavailability of acylguanidine compounds. In comparison, the acylguanidines bearing linear octanoyl chain showed better NA inhibitory activity and higher hydrolysis rate than the corresponding derivatives having bulky branched naproxen moiety. Our molecular docking experiments revealed that the straight octanoyl chain could extend to the 150-cavity and 430-cavity of NA to gain extra hydrophobic interactions. Mice receiving the ZA octanoylguanidine derivative survived from influenza infection better than those treated with ZA, whereas the GOC octanoylguanidine derivative could be orally administrated to treat mice with efficacy equal to oseltamivir. Our present study demonstrates that incorporation of appropriate lipophilic acyl substituents to the polar guanidine group of ZA and GOC is a feasible approach to develop oral drugs for influenza therapy.