Design, synthesis and anti-HBV activity study of novel HBV capsid assembly modulators.

Capsid assembly modulators (CAMs) have the potential to cure chronic hepatitis B, as demonstrated in clinical trials. Lead compounds NVR3-778 and 5a were found to exist in normal and flipped conformations through induced fit docking. Therefore, we designed and synthesized series I and II compounds by interchanging the amide and sulfonamide bonds of 5a to modify both the tolerance region and solvent-opening region. Among them, compound 4a (EC50 = 0.24 ± 0.10 µM, CC50 > 100 µM) exhibited potent anti-HBV activity with low toxicity, surpassing the lead compounds NVR3-778 (EC50 = 0.29 ± 0.03 µM, CC50 = 20.78 ± 2.29 µM) and 5a (EC50 = 0.50 ± 0.07 µM, CC50 = 48.16 ± 9.15 µM) in HepAD38 cells. Additionally, compared with the lead compound, 4a displayed a stronger inhibitory effect on HBV capsid protein assembly. Molecular dynamics (MD) simulations confirmed that the normal conformation of 4a had relatively stable conformation at different frames of binding modes. Furthermore, 4a showed better metabolic stability in human plasma than positive control drugs. Therefore, compound 4a could be further structurally modified as a potent lead compound.

Design, synthesis and biological evaluation of novel dihydrobenzodioxine derivatives as HBV capsid protein inhibitors.

Capsid assembly modulators (CAMs) have recently been revealed to be effective in blocking HBV replication. HBV capsid protein inhibitors reduce and ultimately eliminate HBV by inhibiting virus replication and blocking hepatocyte infection. Sulfonamides are synthetic functional groups in development of different kinds of drugs. Sulfonyl benzamide clinical drugs NVR 3-778 and BA-38017 are lead compounds in discovery of antiviral compounds with increased activity and reduced cytotoxicity by drug design strategies including pharmacophore hybrid, bioisosterism and scaffold hopping. In current study, three series of target compounds were synthesized, and their anti-HBV activity was evaluated against HepAD38 cells. Compound 5a (EC50 = 0.50 ± 0.07 µM, CC50 = 48.16 ± 9.15 µM) showed better anti-HBV DNA replication activity than the lead compound BA-38017, and showed good inhibitory effect on the assembly of HBV capsid protein compared with the clinical drug NVR 3-778. In addition, preliminary structure-activity relationship (SAR) and molecular docking studies were conducted to explore potential interactions and binding modes between compounds and target proteins, which may help researchers to find more effective anti-HBV drugs.

Discovery of potent histone deacetylase inhibitors with modified phenanthridine caps.

In discovery of novel HDAC inhibitory with anticancer potency, pharmacophores of phenanthridine were introduced to the structure of HDAC inhibitors. Fatty and aromatic linkers were evaluated for their solubility and activity. Both enzyme inhibitory and in vitro antiproliferative (against U937 cells) screening results revealed better activities of compounds with aromatic linker than molecules with fatty linker. Compared with SAHA (IC50 values of 1.34, 0.14, 2.58, 0.67 and 18.17 µM), molecule Fb-4 exhibited 0.87, 0.09, 0.32, 0.34 and 17.37 µM of IC50 values against K562, U266, MCF-7, U937 and HEPG2 cells, respectively. As revealed by cell cycle and apoptotic analysis, induction of G2/M phase arrest and apoptosis plays an important role in the inhibition of MCF-7 cells by Fb-4. Generally, a potent HDAC inhibitor was developed in the present study which could be utilised as a lead compound for further anticancer drug design.

Design, Synthesis, and Biological Evaluation of Novel Thioureidobenzamide (TBA) Derivatives as HBV Capsid Assembly Modulators.

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach for the treatment of HBV infection. In this study, we designed and synthesized five series of benzamide derivatives based on a multisite-binding strategy at the tolerant region and diversity modification in the solvent-exposed region. Among them, thioureidobenzamide compound 17i exhibited significantly increased anti-HBV activity in HepAD38 (EC50 = 0.012 µM) and HBV-infected HLCZ01 cells (EC50 = 0.033 µM). Moreover, 17i displayed a better inhibitory effect on the assembly of HBV capsid protein compared with NVR 3-778 and a inhibitory effect similar to the clinical drug GLS4. In addition, 17i showed moderate metabolic stability in human microsomes, had excellent oral bioavailability in Sprague-Dawley (SD) rats, and inhibited HBV replication in the HBV carrier mice model, which could be considered as a promising candidate drug for further development.

The value of dynamic monitoring of procalcitonin in the early identification of pathogens and prognosis of bloodstream infections in the ICU.

BACKGROUND: To explore the value of dynamic monitoring of procalcitonin (PCT) for early identification of pathogens and prognosis of bloodstream infections (BSI) in the intensive care unit (ICU). METHODS: A retrospective analysis was performed on 84 patients with positive blood cultures. Patients were divided into the survival group and death group according to prognosis. Dynamic changes of PCT before and after treatment in the two groups were compared, as well as the relationship between such changes and prognosis. RESULTS: Among the 84 patients with bloodstream infections, 41 cases of Gram-negative (G-) bacteria, 40 cases of Gram-positive (G+) bacteria, and 3 cases of fungi were detected. PCT value in the G- bacteria group was significantly higher than that in the G+ bacteria group and fungus group, and the difference was statistically significant (P<0.05). PCT values on the first day of the G- bacteria group and the non-G- bacteria group were analyzed by a receiver operating characteristic (ROC) curve. When the threshold value was 3.84 ng/mL, the sensitivity, specificity, and area under the ROC curve for predicting G- bacteria bloodstream infection were 61%, 92.5%, and 0.841, respectively. The Kruskal-Wallis test (K-W test) was performed on PCT levels of each G- bacteria on the first day of bloodstream infection, and the difference was not statistically significant (P>0.05). Logistic binary regression analysis showed that the reduction rate of PCT after 5 days of treatment was an independent protective factor for patient survival. ROC curves showed that the sensitivity and specificity for predicting patient survival were 88% and 68.7%, respectively, when the PCT reduction rate (PCT(D1-D5)/D1) reached 36.02% or more. CONCLUSIONS: PCT can be used as an adjunctive method to quickly diagnose pathogenic microorganisms of bloodstream infections, and the anti-infection treatment scheme has certain guiding value. The dynamic changes in PCT have a certain role in predicting the therapeutic effect and prognosis of anti-infection treatment.

Design, diversity-oriented synthesis and biological evaluation of novel heterocycle derivatives as non-nucleoside HBV capsid protein inhibitors.

The capsid assembly is a significant phase for the hepatitis B virus (HBV) lifespan and is an essential target for anti-HBV drug discovery and development. Herein, we used scaffold hopping, bioisosterism, and pharmacophore hybrid-based strategies to design and synthesize six series of various heterocycle derivatives (pyrazole, thiazole, pyrazine, pyrimidine, and pyridine) and screened for in vitro anti-HBV non-nucleoside activity. Drug candidate NZ-4 and AT-130 were used as lead compounds. Several compounds exhibited prominent anti-HBV activity compared to lead compound NZ-4 and positive drug Lamivudine, especially compound II-8b, showed the most prominent anti-HBV DNA replication activity (IC50 = 2.2 ± 1.1 µM). Also compounds IV-8e and VII-5b showed the best in vitro anti-HBsAg secretion (IC50 = 3.8 ± 0.7 µM, CC50 > 100 µM) and anti-HBeAg secretion (IC50 = 9.7 ± 2.8 µM, CC50 > 100 µM) respectively. Besides, II-8b can interact HBV capsid protein with good affinity constants (KD = 60.0 µM), which is equivalent to lead compound NZ-4 ((KD = 50.6 µM). The preliminary structure-activity relationships (SARs) of the newly synthesized compounds were summarized, which may help researchers to discover more potent anti-HBV agents.

Design, synthesis, and evaluation of novel heteroaryldihydropyrimidine derivatives as non-nucleoside hepatitis B virus inhibitors by exploring the solvent-exposed region.

In continuation of our efforts toward the discovery of potent non-nucleoside hepatitis B virus (HBV) inhibitors with novel structures, we have explored the solvent-exposed protein region of heteroaryldihydropyrimidine derivatives. Herein, the morpholine ring of GLS4 was replaced with substituted sulfonamides and triazoles to generate novel non-nucleoside HBV inhibitors with desirable potency. In in vitro biological evaluation, several derivatives showed good anti-HBV DNA replication activity compared to lamivudine. In particular, compound II-1 displayed the most potent activity against HBV DNA replication (IC50  = 0.35 ± 0.04 µM). The preliminary structure-activity relationships of the new compounds were summarized, which may help in discovering more potent anti-HBV agents via rational drug design.

A green and facile synthesis of an industrially important quaternary heterocyclic intermediates for baricitinib.

BACKGROUND: Baricitinib, with a 2-(1-(ethylsulfonyl)azetidin-3-yl)acetonitrile moiety at N-2 position of the pyrazol skeleton, is an oral and selective reversible inhibitor of the JAK1 and JAK2 and displays potent anti-inflammatory activity. Several research-scale synthetic methods have been reported for the preparation of key quaternary heterocyclic intermediates of baricitinib. However, they were all associated with several drawbacks, such as the expensive materials, usage of pollutional reagents, and poor yields. RESULTS: In this manuscript, we established a green and cost-effective synthesis of 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate for further scale-up production of baricitinib. This synthetic method employs commercially available and low-cost starting material benzylamine and an industry-oriented reaction of green oxidation reaction in microchannel reactor to yield important quaternary heterocyclic intermediates. CONCLUSION: Generally, this procedure is reasonable, green and suitable for industrial production.

Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant.

Due to the emergence of highly pathogenic and oseltamivir-resistant influenza viruses, there is an urgent need to develop new anti-influenza agents. Herein, five subseries of oseltamivir derivatives were designed and synthesized to improve their activity toward drug-resistant viral strains by further exploiting the 150-cavity in the neuraminidases (NAs). The bioassay results showed that compound 21h exhibited antiviral activities similar to or better than those of oseltamivir carboxylate (OSC) against H5N1, H5N2, H5N6, and H5N8. Besides, 21h was 5- to 86-fold more potent than OSC toward N1, N8, and N1-H274Y mutant NAs in the inhibitory assays. Computational studies provided a plausible rationale for the high potency of 21h against group-1 and N1-H274Y NAs. In addition, 21h demonstrated acceptable oral bioavailability, low acute toxicity, potent antiviral activity in vivo, and high metabolic stability. Overall, the above excellent profiles make 21h a promising drug candidate for the treatment of influenza virus infection.

Optimization of N-Substituted Oseltamivir Derivatives as Potent Inhibitors of Group-1 and -2 Influenza A Neuraminidases, Including a Drug-Resistant Variant.

On the basis of our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80-12.47 and 1.20-3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.

Design, synthesis and primary biological evaluation of the novel 2-pyridone derivatives as potent non-nucleoside HBV inhibitors.

In continuation of our efforts toward the discovery of potent non-nucleoside hepatitis B virus (HBV) inhibitors with novel structures, we have employed bioisosterism and hybrid pharmacophore-based strategy to explore the chemically diverse space of bioactive compounds. Cytotoxicity, anti-HBV antigen secretion activities and anti-HBV DNA replication activity were assayed with cell counting kit-8 (CCK-8), enzyme linked immunosorbent assay (ELISA) and a real-time PCR, respectively. Some of the new compounds were able to inhibit the replication of HBV DNA activity in the low micromolar range. In particular, compound 8u displayed the most potent activity against the replication of HBV DNA with IC50 value of 3.4 µM. The preliminary structure-activity relationship (SAR) of these new compounds was investigated, which may help designing more potent molecules.

Design, synthesis and evaluation of pyrazole derivatives as non-nucleoside hepatitis B virus inhibitors.

In continuation of our efforts toward the discovery of potent non-nucleoside hepatitis B virus (HBV) inhibitors with novel structures, we have employed bioisosterism and hybrid pharmacophore-based strategy to explore the chemically diverse space of bioactive compounds. In this article, the original thiazole platform was replaced with pyrazole scaffold to yield the optimal pharmacophore moieties in order to generate novel non-nucleoside HBV inhibitors with desirable potency. Some of the new compounds were able to inhibit HBV activity in the low micromolar range. In particular, compound 6a3 displayed the most potent activity against the secretion of HBsAg and HBeAg with IC50 of 24.33 µM and 2.22 µM, respectively. The preliminary structure-activity relationship (SAR) of this new series of compounds was investigated, which may help designing more potent molecules.

A comparison of postoperative early enteral nutrition with delayed enteral nutrition in patients with esophageal cancer.

We examined esophageal cancer patients who received enteral nutrition (EN) to evaluate the validity of early EN compared to delayed EN, and to determine the appropriate time to start EN. A total of 208 esophagectomy patients who received EN postoperatively were divided into three groups (Group 1, 2 and 3) based on whether they received EN within 48 h, 48 h-72 h or more than 72 h, respectively. The postoperative complications, length of hospital stay (LOH), days for first fecal passage, cost of hospitalization, and the difference in serum albumin values between pre-operation and post-operation were all recorded. The statistical analyses were performed using the t-test, the Mann-Whitney U test and the chi square test. Statistical significance was defined as p < 0.05. Group 1 had the lowest thoracic drainage volume, the earliest first fecal passage, and the lowest LOH and hospitalization expenses of the three groups. The incidence of pneumonia was by far the highest in Group 3 (p = 0.019). Finally, all the postoperative outcomes of nutritional conditions were the worst by a significant margin in Group 3. It is therefore safe and valid to start early enteral nutrition within 48 h for postoperative esophageal cancer patients.

The Changing Face of Hepatitis C: Recent Advances on HCV Inhibitors Targeting NS5A

Current treatment for HCV infections consists of approved direct acting antivirals (DAAs), viz. the protease inhibitors (boceprevir, telaprevir, and simeprevir), NS5B polymerase inhibitors (sofosbuvir) and NS5A inhibitor (ledipasvir) in combination with pegylated interferon α and ribavirin). These treatments have made a great improvement in the treatment of chronic HCV infections in recent years, but their adverse side effects, emergence of resistant mutants, high cost, and increased pill burden have limited their clinical use. Recently, with the increasing knowledge in understanding the HCV life cycle, more targets have been recognized. NS5A protein plays a critical role in assembly of infectious HCV particles and offering potential for HCV therapies. Therefore, discovery and development of novel DAAs targeting NS5A with novel mechanisms of action, is of great necessity to improve the quality of existing HCV treatments. In the present review, we discuss recent advances with NS5A inhibitors with potent anti-HCV activity, and the potential for the development of HCV NS5A inhibitors to combat HCV infections.

Recent advance of the hepatitis B virus inhibitors: a medicinal chemistry overview.

Hepatitis B Virus (HBV) is one of the most prevalent viral infections of human worldwide. The therapies are limited in the clinical context because of negative side effects of interferons and the development of viral resistance to the nucleoside/nucleotide inhibitors. In this review, we summarize the recent advances in design and development of potent anti-HBV inhibitors from natural sources and synthetic compounds, targeting different steps in the life cycle of HBV. We attempt to emphasize the major structural modifications, mechanisms of action and computer-aided docking analysis of novel potent inhibitors that need to be addressed in the future to design potent anti-HBV molecules.