The current strategies of optimization of oseltamivir against mutant neuraminidases of influenza A：A review.

Influenza with a tendency to cause pandemic and epidemic is an infectious disease with a high of morbidity and mortality. Neuraminidase (NA) inhibitors are proved to prevent and treat influenza. Among the four Neuraminidase inhibitors (NAIs) licensed, oseltamivir is most commonly used. With the extensive usage, several variants containing mutant NAs especially H274Y point mutation exhibit reduced susceptibility. In this review, we covered the current drugs available for influenza, the analysis of active site of NA, the mutant types of NAs and the molecular mechanism of drug resistance brought by H274Y mutant NAs. For recovering the susceptibility to oseltamivir, many series of oseltamivir analogues were designed. We present the details of the strategies of strengthening the interactions with S2 via introducing strong basic fragment, targeting additional subpockets and making full use of Zone X by modifying 3-pentyl of OC. PROTAC targeting NA and combination therapies are also introduced. Further, the advantages and disadvantages of these methods are also discussed.

Discovery of hydrazide-containing oseltamivir analogues as potent inhibitors of influenza A neuraminidase.

Neuraminidase (NA) inhibitors play a prime role in treating influenza. However, a variety of viruses containing mutant NAs have developed severe drug resistance towards NA inhibitors, so it is of crucial significance to solve this problem. Encouraged by urea-containing compound 12 disclosed by our lab, we designed a series of oseltamivir derivatives bearing hydrazide fragment for targeting the 150 cavity. Among the synthesized compounds, compound 17a showed 8.77-fold, 4.12-fold, 203-fold and 6.23-fold more potent activity than oseltamivir carboxylate against NAs from H5N1, H1N1, H5N1-H274Y, H1N1-H274Y, respectively. Meanwhile, the best compound 17a exhibited satisfactory metabolic stability in vitro. This study offers an important reference for the structural optimization of oseltamivir aiming at potent inhibition against H274Y mutant of NAs.

Discovery of a non-zwitterionic oseltamivir analogue as a potent influenza a neuraminidase inhibitor.

The most of potent neuraminidase inhibitors as zwitterions with poor lipophilicity suffered from the poor oral bioavailability. Herein, we describe a rational journey to discover a non-zwitterionic neuraminidase inhibitor 24a containing urea. It showed potent inhibitions against neuraminidases from group 1(H5N1 and H1N1) and group 2 (H3N2) subtypes and exhibited more strong inhibitory activities against neuraminidases from H274Y mutants than oseltamivir carboxylate. Whether administrated by orally or intravenous injection, the pharmacokinetic profile of compound 24a in SD rats were improved compared to oseltamivir carboxylate.

Application of carbamyl in structural optimization.

Carbamyl is considered a privileged structure in medicinal chemistry. It has a wide range of biological activities such as antimicrobial, anticancer, anti-epilepsy, for which the best evidence is a number of marketed carbamyl-containing drugs. Carbamyl is formed of primary amine and carbonyl moieties that act as hydrogen bond donors and hydrogen acceptors with residues of targets respectively, which are benefit for improving pharmacological activities. In other cases, the introduced carbamyl improves drug-like properties including oral bioavailability. In this review, we introduce the carbamyl-containing drugs and the application of carbamyl in structural optimization as a result of enhancing activities or/and drug-like properties.

Design, synthesis and biological evaluation of oseltamivir derivatives containing pyridyl group as potent inhibitors of neuraminidase for influenza A.

Influenza A neuraminidase plays an indispensable role in the process of replication and transmission of influenza, so the neuraminidase inhibition can prevent the reproduction of the viruses therefore achieve the effect of treatment of influenza. However, drug resistance of neuraminidase inhibitors such as oseltamivir highlights the need to develop novel structural neuraminidase inhibitors. Here we explored a series of oseltamivir derivatives bearing pyridyl group. Among them, compound 23b exhibiting potent inhibitory activity against neuraminidase from H5N1 subtype was comparable to oseltamivir carboxylate. Cytopathic effect inhibition assay in MDCK cells indicated that compound 23b exerted powerful inhibitions on influenza viruses. And compound 23b were nontoxic to MDCK cells. Meanwhile, compound 23b showed high stability towards rat liver microsomes, human liver microsomes and human plasma. This research enriched the structural type of neuraminidase inhibitors.

Synthesis and Biological Evaluation of NH2-Sulfonyl Oseltamivir Analogues as Influenza Neuraminidase Inhibitors.

A series of NH2-sulfonyl oseltamivir analogues were designed, synthesized, and their inhibitory activities against neuraminidase from H5N1 subtype evaluated. The results indicated that the IC50 value of compound 4a, an oseltamivir analogue via methyl sulfonylation of C5-NH2, was 3.50 µM. Molecular docking simulations suggested that 4a retained most of the interactions formed by oseltamivir carboxylate moieties and formed an additional hydrogen bond with the methylsulfonyl group. Meanwhile, 4a showed high stability towards human liver microsomes. More importantly, 4a without basic moieties is not a zwitterion as reported on the general structure of neuraminidase inhibitors. This research will provide valuable reference for the research of new types of neuraminidase inhibitors.

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 ±â€¯0.23 µM), and it targeted the recently discovered 430-cavity. Compound 5m (LogD = -0.12) is more lipophilic than oseltamivir carboxylate (LogD = -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.

Synthesis and biological evaluation of NH2-acyl oseltamivir analogues as potent neuraminidase inhibitors.

Neuraminidase inhibitors can deter nascent viruses from infecting intact cells by preventing their release from host cells. Herein, a neuraminidase inhibitor 11b absent of basic moieties was discovered in the process of searching for inhibitors targeting 150 cavity. It exhibited potent inhibitions against wild-type neuraminidases from group 1 (H5N1 and H1N1) and group 2 (H7N9) subtypes with IC50 values similar to those of oseltamivir carboxylate. Moreover, 11b showed moderate inhibitions against mutant neuraminidases from H5N1-H274Y and H1N1-H274Y with IC50 values of 2075 nM and 1382 nM, which were inferior to those of oseltamivir carboxylate (6095 nM and 4071 nM). The results were not consistent with the recognized SARs that a basic moiety was an indispensable part of a potent inhibitor.

Preparation and in vitro/in vivo evaluation of revaprazan hydrochloride nanosuspension.

Revaprazan hydrochloride (RH) is a new reversible proton pump inhibitor. However, due to poor water solubility, oral bioavailability of the drug was relatively low. To investigate the particle size reduction effect of RH on dissolution and absorption, three suspensions that containing different sized particles were prepared by high pressure homogenization and in vitro/in vivo evaluations were carried out. DSC and powder X-ray diffraction were used to study crystalline state of freeze dried powder of RH suspensions and the results showed that particles of RH microsuspension and nanosuspension remained in the same crystalline state as coarse suspension, but had lower lattice energy. In the in vitro dissolution test, both microsuspension and nanosuspension showed increased dissolution rate. In the in vivo evaluation, compared to coarse suspension, RH nanosuspension exhibited significant increase in AUC(0-t), C(max) and decrease in T(max), MRT. Nevertheless, RH microsuspension did not display any significant differences in these pharmacokinetic parameters compared to the coarse suspension. The findings revealed that particle size reduction can influence RH absorption in gastrointestinal tract and nanosuspension can enhance oral bioavailability of RH in rats.

Asymmetric synthesis of (-)-swainsonine.

We report a new asymmetric synthetic method for (-)-swainsonine utilizing a chiral oxazoline precursor. The key features in this strategy are the diastereoselective oxazoline formation reaction catalyzed by palladium(0), diasteroselective dihydroxylation, and the stereocontrolled allylation reaction with TiCl(4).

Stereoselective synthesis of (+)-polyoxamic acid based on the synthesis of chiral oxazine.

A concise, stereocontrolled synthesis of (+)-polyoxamic acid was achieved. Starting from trans-oxazoline as a chiral building block, the key step involves diastereoselective oxazine formation catalyzed by palladium(0).

Application of Pd(0)-catalyzed intramolecular oxazine formation to the efficient total synthesis of (-)-anisomycin.

The enantioselective total synthesis of (-)-anisomycin, a potent antibiotic agent, has been achieved. The key steps are a Pd(0)-catalyzed stereoselective intramolecular oxazine formation from d-tyrosine and pyrrolidine formation by catalytic hydrogenation of the oxazine.

A concise synthesis of a promising protein kinase C inhibitor: D-erythro-sphingosine.

In this study, we explored a convenient and concise route for synthesis of D-erythro-sphingosine 1 from commercially available and cheap L-serine. The key steps are simple preparation of amino ketone 5 from Weinreb amide 3 and high diastereoselective reduction of amino ketone 5 to give the natural erythro-(anti-) isomer.

Stereoselective synthesis of L-threo-sphingosine, L-threo-sphinganine, D-threo-sphingosine, and D-threo-sphinganine via oxazoline formation and olefin cross-metathesis; potent protein kinase C inhibitor analogues.

In this study, we explored a convenient and concise route for synthesis of L-threo-sphingosine, D-threo-sphingosine, L-threo-sphinganine and D-threo-sphinganine from commercially available L- or D-serine. The key steps are the simple preparation of trans-oxazoline and intermolecular olefin cross metathesis.