The 8-bromobaicalein alleviated chikungunya-induced musculoskeletal inflammation and reduced the viral load in healthy adult mice

ABSTRACTChikungunya virus is a re-emerging arbovirus that has caused epidemic outbreaks in recent decades. Patients in older age groups with high viral load and severe immunologic response during acute infection are likely to develop chronic arthritis and severe joint pain. Currently, no antiviral drug is available. Previous studies suggested that a flavone derivative, 8-bromobaicalein, was a potential dengue and Zika replication inhibitor in a cell-based system targeting flaviviral polymerase. Here we characterized that 8-bromobaicalein inhibited chikungunya virus replication with EC50 of 0.49 ± 0.11 µM in Vero cells. The molecular target predicted at viral nsP1 methyltransferase using molecular binding and fragment molecular orbital calculation. Additionally, oral administration of 250 mg/kg twice daily treatment alleviated chikungunya-induced musculoskeletal inflammation and reduced viral load in healthy adult mice. Pharmacokinetic analysis indicated that the 250 mg/kg administration maintained the compound level above EC99.9 for 12 h. Therefore, 8-bromobaicalein should be a potential candidate for further development as a pan-arboviral drug

Discovery of 3-chlorobenzyl-linked 1,9-diazaspiro[5.5]undecane derivatives, a lead for dengue virus type 2 infection

Dengue virus poses a serious worldwide health threat with up to 400 million infections occurring annually in over 100 countries. Currently, there are no specific therapeutics available, and the only Licensed vaccine is used to mitigate the risk of hospitalization in immunologically naive individuals. In the current work, for the first time we are reporting dengue virus type 2 (DENV2) inhibitory activity in newly designed 3-chLorobenzyL-Linked 1,9-diazaspiro[5.5]undecane derivatives. Compounds with substitutions featuring 2-methyLbenzyL (SPO 6, EC50 = 11.43 +/- 0.87 mu M), 4-bromobenzyL (SPO 7, EC50 = 14.15 +/- 0.50 mu M), and 4-cyanobenzyl (SPO-13, EC50 = 20.77 +/- 1.92 mu M) groups and the antiviral drug ribavirin (IC50 = 50.9 +/- 18 mu M, J. Gen. Virol., 2006, 87, 1947-1952) were found to be potent against DENV2 in a cell-based assay. Docking calculations identified NS5-methyLtransferase as the most probable target for this series of compounds. Molecular dynamics simulations of NS5-methyLtransferase reproduced the experimental binding affinity findings by yielding Delta G(bind) values that predicted SPO-6 to possess the most favorable binding energy of -27.2 +/- 3.9 kcaL mol(-1) compared with SPO-7, SPO-13 and ribavirin with -22.5 +/- 4.7, -22.5 +/- 4.6 and -20.0 +/- 4.6 kcaL mol(-1), respectively. In addition, based on Lipinski's rule of five, SPO-6 was found to be non-toxic and possessed a better drug-Likeness score (5.87) in comparison with the standard drug ribavirin (1.72)

Lichen-Derived Diffractaic Acid Inhibited Dengue Virus Replication in a Cell-Based System

10.3390/molecules28030974MOLECULES28

The 8-bromobaicalein inhibited the replication of dengue, and Zika viruses and targeted the dengue polymerase

Abstract Dengue and Zika viruses are mosquito-borne flaviviruses burdening millions every year with hemorrhagic fever and neurological symptoms. Baicalein was previously reported as a potential anti-flaviviral candidate and halogenation of flavones and flavanones potentiated their antiviral efficacies. Here, we reported that a chemically modified 8-bromobaicalein effectively inhibited all dengue serotypes and Zika viruses at 0.66–0.88 micromolar in cell-based system. The compound bound to dengue serotype 2 conserved pocket and inhibited the dengue RdRp activity with 6.93 fold more than the original baicalein. Moreover, the compound was mildly toxic against infant and adult C57BL/6 mice despite administering continuously for 7 days. Therefore, the 8-bromobaicalein should be investigated further in pharmacokinetics and efficacy in an animal model