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.

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.

[Pilot Study on Start-up and Stable Operation at Low Temperature Based on Denitrifying Phosphorus Removal].

In order to understand the denitrifying and phosphorus removal characteristics of denitrifying phosphate-accumulating organisms (DPAOs), a pilot scale (20 m3) denitrifying and phosphorus removal experiment was carried out using a modified University of Cape Town (UCT) process at low temperatures of (6-16)℃. The test results show that at such temperatures, the hydraulic retention time (HRT) is 20 h and the solids retention time (SRT) is 35 days, and the modified UCT process can start up successfully and run steadily. When running steadily, the system can maintain nitrogen and phosphorus removal rates of 60%±5% and 80%±5%, respectively. The effluent concentrations of chemical oxygen demand (COD), ammonium nitrogen (NH4+-N), total nitrogen (TN), and total phosphorus (TP) were 20, 5, 11, and 0.5 mg·L-1, respectively, which meet the first A emission standard of "Pollutant Discharge Standard for Urban Sewage Treatment Plant" (GB 18918-2002). In order to further investigate the characteristics of nitrogen and phosphorus removal in the system, the reflux ratio from the aerobic tank to the anoxic tank was increased to 150%. After the system was stabilized, it obtained higher nitrogen and phosphorus removal rates of 80%±10% and 90%±5%, respectively. Among them, denitrifying phosphorus removal in the anoxic tank accounted for 80%±4% of the total biological phosphorus removal. The average effluent concentrations of COD, NH4+-N, TN, and TP were 19.55, 0.1, 7.8, and 0.15 mg·L-1, respectively, which meet the Beijing Standard A discharge standard.