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The discovery of novel tetrahydropyrrolo[1,2-c]pyrimidines derivatives from Bay41_4109 as hepatitis B virus (HBV) inhibitors is herein reported. The structure–activity relationship optimization led to one highly efficacious compound 28a (IC50 = 10 nM) with good PK profiles and the favorite L/P ratio. The hydrodynamic injection model in mice clearly demonstrated the efficacy of 28a against HBV replication.

The study of iron chelators as cancer chemotherapeutic agents is still in its infancy. Accordingly, there is a need to optimize new chelating molecules for iron chelation therapy and cancer treatment. Previous studies have demonstrated that the ligand tris(1-pyrazolyl) borohydride and its derivates were able to chelate ferrous iron, but very little research focused on their biological properties and applications in cancer treatment. So, in this study, several boron-pyrazole derivatives were chosen for the examination of their effects on the proliferation of human hepatocellular carcinoma (HCC) cell lines. The results suggested that potassium tris(4-methyl-1-pyrazolyl) borohydride (KTp(4-Me)) exhibited the most potent anti-tumor activities among the candidates. Hence, the antiproliferative activity and the iron chelating capacity of the iron chelator KTp(4-Me) in HCC cell lines HepG2 and Hep3B were characterized. KTp(4-Me) could disrupt cell iron uptake and affect signaling pathways of iron regulation in HCC cell lines and induced the expression of TfR1 and HIF-1α in a concentration-dependent manner, which was a typical cell response to iron deficiency. Moreover, KTp(4-Me) arrested cell cycle in S phase and induced cell apoptosis in both Hep3B and HepG2 cells. Overall, our results provide a promising starting point and the possibility of the future development and applications of KTp(4-Me) in HCC therapy.

Malaria is one of the most devastating infectious diseases in the developing world. Until now, only one candidate malaria vaccine RTS,S/AS01 has shown modest protection in phase 3 trial in African infants. Hence the treatment of malaria still depends on the current chemotherapeutic drugs. Considering the resistance of malaria parasites to almost all used antimalarial drugs, aiming at multi-targets rather than a single target will be a more promising strategy. Previous studies have shown that myricetin and fisetin exhibited in vitro antimalarial activity against Plasmodium falciparum, but very little research focused on the molecular mechanism for their parasiticidal activity. The cysteine protease falcipain-2 and aspartic protease plasmepsin II have long been considered as important antimalarial drug targets, especially combined inhibition of these two proteases. In this study, we determined that myricetin and fisetin are dual inhibitors of falcipain-2 and plasmepsin II, which might account for their antimalarial properties. Overall, the dual inhibition of falcipain-2 and plasmepsin II by myricetin and fisetin has shed light on a possible mechanism for their antimalarial activity and provided a rationale for further development as antimalarial drugs.

This study applied an efficient virtual screening strategy integrating molecular docking with MM-GBSA rescoring to identify diverse human dihydroorotate dehydrogenase (hDHODH) inhibitors. Eighteen compounds with IC(50) values ranging from 0.11 to 18.8 μM were identified as novel hDHODH inhibitors that exhibited overall species-selectivity over Plasmodium falciparum dihydroorotate dehydrogenase (pfDHODH). Compound 8, the most potent one, showed low micromolar inhibitory activity against hDHODH with an IC(50) value of 0.11 μM. Moreover, lipopolysaccharide-induced B-cell assay and mixed lymphocyte reaction assay revealed that most of the hits showed potent antiproliferative activity against B and T cells, which demonstrates their potential application as immunosuppressive agents. In particular, compound 18 exhibited potent B-cell inhibitory activity (IC(50) = 1.78 μM) and presents a B-cell-specific profile with 17- and 26-fold selectivities toward T and Jurkat cells, respectively.

Poly (N-ethyl-4-vinylpyridiniumbromide) (PEVP) was synthesized by the reaction between poly (4-vinylpyridine) (P4VP) and ethyl bromide, and polyelectrolyte complexes (PECs) based on PEVP and sodium carboxymethyl cellulose (CMCNa) were prepared in HCl aqueous solutions. The ionic complexation degrees (ICD) of PECs can be effectively controlled by tuning either quaternization degree (QD) of PEVP polycation or carboxylate group (–COO–) content on CMCNa polyanion, which was characterized by elemental analysis (EA) and Fourier transform infrared (FT-IR). The dilute solution viscosity behavior of PECs was investigated by Ubbelohde viscometer. The hydrophilicity and surface morphologies of polyelectrolyte complex membranes (PECMs) were examined by contact angle meter and field emission scanning electron microscopy (FESEM), respectively. The PECMs were subjected to dehydration of ethanol and showed very high separation performance. Interestingly, the permeation flux of PECMs increased while water content in permeate decreased with increasing ICD. The performance was discussed in terms of the unique structural characteristics of PEVP, PECs and PECMs.

The self-assembly and disintegration behavior of polyzwitterion, poly(4-vinylpyridiniomethanecarboxylate) (PVPMC), and negatively charged polyelectrolyte, poly(acrylic acid) (PAA), layer-by-layer (LbL) multilayer films were investigated in detail by using UV-vis absorption spectroscopy, quartz crystal microbalance (QCM) and atomic force microscopy (AFM). The results indicated that the PVPMC/PAA multilayer films grew linearly with increasing bilayer number. The disintegration rate of PVPMC/PAA multilayers could be well controlled by varying the concentration of salt in aqueous solution. It was found that PVPMC/PAA multilayer films could be completely disintegrated in 0.9% normal saline solution within 15 min. Such controllable disintegration behavior rendered the PVPMC/PAA multilayer as an excellent sacrificial sublayer for fabricating free-standing LbL multilayer films. Free-standing multilayer films were then successfully fabricated by LbL self-assembly of positively charged polyelectrolyte complex (PEC), made from poly(diallyldimethylammonium) (PDDA) and poly(sodium 4-styrenesulfonate) (PSS), and negatively charged PSS with PVPMC/PAA as a sacrificial sublayer, which was disintegrated in 0.9% normal saline solution. The obtained free-standing films had good mechanical properties with 24.1 MPa tensile strength at break and 0.56 GPa Young's modulus.

Soluble polyelectrolyte complexes (PECs) between chitosan (CS) and sodium carboxymethyl cellulose (CMCNa) were synthesized in aqueous hydrochloric acid (HCl) and obtained in their solid form. FT-IR, elemental analysis (EA), thermal gravity analysis (TGA), wide-angle X-ray diffraction (WAXD), and viscometry were used to characterize the chemical structure, composition, thermal stability, crystallinity and solution property of PECs, respectively. These PECs could be dissolved in aqueous NaOH and their homogeneous polyelectrolyte complex membranes (HPECMs) were made by solution casting method. Both the surface morphology of HPECMs and the morphology of single PEC aggregate were examined by field emission scanning electron microscope (FESEM), and atomic force microscopy (AFM). Effects of the water content in aqueous ethanol and temperature on the swelling behavior and pervaporation dehydration of HPECM were examined. A good performance of J = 1.14 kg/m2 h, α = 1062 was obtained with HPECM0.25 in dehydrating 10 wt.% water–ethanol at 70 °C. The swelling behavior and pervaporation performance were interpreted in terms of structure characteristics of both PECs and HPECMs.

Polyelectrolyte complexes (PECs) between poly(diallyldimethylammonium chloride) (PDDA) and sodium carboxymethyl cellulose (CMCNa) with four ionic complexation degrees (ICD) were synthesized and their homogeneous polyelectrolyte complex membranes (HPECMs) were fabricated. Elemental analysis and FT-IR were used to determine the composition and chemical structure of PECs. Thermogravimetric analysis (TGA), wide-angle X-ray diffraction (WAXD) and viscometry were used to characterize the thermal stability, crystallinity and solution properties of PECs, respectively. Field emission scanning electron microscope (FESEM) was used to examine the surface morphology of HPECMs, which were subjected to the pervaporation dehydration of isopropanol. Effects of membrane fabrication methods, cycling of feed temperature and ICD of PECs on pervaporation performance of HPECMs are discussed. Meanwhile, HPECMs were also subjected to dehydration of three other organics and showed very good performance. All these performances are explained in terms of the unique structural characteristics of PECs and HPECMs.

Polyethylenimine/poly(acrylic acid sodium salt) (PEI/PAA) ultrathin polyelectrolyte multilayer membranes were fabricated by an electric field enhanced method and were used for isopropanol/water pervaporation. Surface properties of the electric field enhanced multilayer polyelectrolyte membranes (EPEMs) prepared under different conditions were investigated by atomic force microscopy (AFM) and contact angle (CA) measurements. It was found that surface properties (roughness and hydrophilicity) of EPEMs strongly depend on the direction of the electric field, dipping time, applied voltage, number of bilayers, which, in turn, affect their pervaporation performance. The (PEI/PAA)4PEI EPEMs fabricated with a dipping time of 15 min and an applied voltage of 5 V for separating 10 wt% water–isopropanol mixtures exhibited high separation factor and large flux. Meanwhile, the performance of the EPEMs displays good storage stability within 60 days.

Plasmepsin II (PM II) is an attractive target for anti-malaria drug discovery, which involves in host hemoglobin degradation in the acidic food vacuole. In this study, we demonstrated the successful use of structure-based virtual screening to identify inhibitors of PM II from two chemical database. Five novel non-peptide inhibitors were identified and revealed moderate inhibitory potencies with IC50 ranged from 4.62 ± 0.39 to 9.47 ± 0.71 μM. The detailed analysis of binding modes using docking simulations for five inhibitors showed that the inhibitors could be stabilized by forming multiple hydrogen bonds with catalytic residues (Asp 34 and Asp 214) and also with other key residues.