Design, Synthesis, and Evaluation of Tetrahydropyrrolo[1,2-c]pyrimidines as Capsid Assembly Inhibitors for HBV Treatment.

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.

Antiproliferative activity and therapeutic implications of potassium tris(4-methyl-1-pyrazolyl) borohydride in hepatocellular carcinoma.

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.

Dietary flavonoids fisetin and myricetin: dual inhibitors of Plasmodium falciparum falcipain-2 and plasmepsin II.

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.

Discovery of non-peptide inhibitors of Plasmepsin II by structure-based virtual screening.

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.

Discovery of diverse human dihydroorotate dehydrogenase inhibitors as immunosuppressive agents by structure-based virtual screening.

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.