ABSTRACT
Dengue fever is one of the most important vector-borne human diseases caused by mosquito vectorAedes aegypti and Aedes albopictus. Dengue virus can cause dengue fever, dengue hemorrhagic fever and dengue shock syndrome. There are no approved drugs for the treatment of dengue disease so far. According to the mechanism of anti-dengue virus(anti-DENV) action, drugs under development for dengue disease can be divided into two categories: viral replication inhibitors and anti-cell factor pathway inhibitors. The former is further divided into DENV entry inhibitors, capsid protein inhibitors, NS3 protein inhibitors, NS5 protein inhibitors, and NS4B protein inhibitors; the latter is further divided into cell receptor inhibitors, lipid synthesis and metabolism inhibitors, and glucosidase inhibitors. The R&D of anti-DENV drugs is facing enormous challenges. Development of effective drugs which can be used for the treatment of four serotypes of dengue has a broad application prospect, and it will bring new hopes for dengue fever prevention and therapy.
ABSTRACT
To evaluate the anti-HIV-1 activities of 5 benzophenones non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as DY1203, DY1204, DY1119, DY1208 and DY1209 in vitro, the cytotoxicity of 5 compounds were tested on C8166, MT-4, H9 and PBMC with the MTT assay. The anti-HIV-1 activities of compounds were evaluated on laboratory-adapted strain, drug-resistant strains and primary isolated strains by p24 antigen expression ELISA. The inhibition of HIV-1 recombinant reverse transcriptase activity was assessed by ELISA assay. Among 5 compounds, DY1203 and DY1204 showed low cytotoxicities with CC50 greater than 200 μg·mL-1. DY1119, DY1208 and DY1209 showed strong anti-HIV-1 activities against HIV-1IIIB, HIV-174V, HIV-1RF/V82F/184V, HIV-1NL4-3 gp41(36G) N42S, HIV-1KM018, HIV-1TC-1 and HIV-1Wan. However, NNRTIs drug-resistant strain HIV-1A17 showed different resistance to these compounds. The 5 compounds proved active against HIV-1 recombinant reverse transcriptase. DY1208 is expected to become a new lead compound for its high therapeutic index. The results can provide new information for HIV-1 drug research and promote the development of new HIV-1 drugs.
ABSTRACT
It was recently shown that several new synthetic 2-alkylsulfanyl-6-benzyl-3, 4-dihydropyrimidin-4(3H)-one (S-DABO) derivatives demonstrated anti-HIV-1 activity. Three of the derivatives namely RZK-4, RZK-5 and RZK-6 were used in this study to explore their inhibitory effects on a variety of HIV strains. These compounds at a concentration of 200 microg mL(-1) almost completely inhibited the activity of recombinant HIV-1 reverse transcriptase. All of the three compounds reduced replication of HIV-1 laboratory-derived strains, low-passage clinical isolated strain, and the drug resistant strain. In particular RZK-6 showed potent activity against the HIV-1 drug resistant strain. In general, the antiviral activities are similar in magnitude to nevirapine (NVP), which is a non-nucleoside reverse transcriptase inhibitor approved by FDA. The therapeutic indexes of these compounds were remarkable, ranging from 3704 to 38462 indicating extremely low cytotoxicity. These results suggest that the three S-DABO derivatives in this study have good potential for further development in anti-HIV-1 therapy. It may be particularly useful to target at the non-nucleoside reverse transcriptase inhibitors resistant HIV-1 strain.