Chronic Hepatitis B virus (HBV) infection is a major worldwide public health problem. Current direct-acting anti-HBV drugs target the HBV DNA polymerase activity, but the equally essential viral ribonuclease H (RNaseH) activity is unexploited as a drug target. Previously, we reported that α–hydroxytropolone compounds can inhibit the HBV RNaseH and block viral replication. Subsequently, we found that our biochemical RNaseH assay underreports efficacy of the α-hydroxytropolones against HBV replication. Therefore, we conducted a structure-activity analysis of 59 troponoids against HBV replication in cell culture. These studies revealed that antiviral efficacy is diminished by larger substitutions on the tropolone ring, identified key components in the substitutions needed for high efficacy, and revealed that cytotoxicity correlates with increased lipophilicity of the α-hydroxytropolones. These data provide key guidance for further optimization of the α-hydroxytropolone scaffold as novel HBV RNaseH inhibitors.
A library of α-hydroxytropolones synthesized through a simple halogenation/thiolate addition sequence reveals molecules with potent activity against three human pathogens.
Rift Valley fever virus (RVFV) is a veterinary and human pathogen and is an agent of bioterrorism concern. Currently, RVFV treatment is limited to supportive care, so new drugs to control RVFV infection are urgently needed. RVFV is a member of the order Bunyavirales, whose replication depends on the enzymatic activity of the viral L protein. Screening for RVFV inhibitors among compounds with divalent cation-coordinating motifs similar to known viral nuclease inhibitors identified 47 novel RVFV inhibitors with selective indexes from 1.1-103 and 50% effective concentrations of 1.2-56 μM in Vero cells, primarily α-Hydroxytropolones and N-Hydroxypyridinediones. Inhibitor activity and selective index was validated in the human cell line A549. To evaluate specificity, select compounds were tested against a second Bunyavirus, La Crosse Virus (LACV), and the flavivirus Zika (ZIKV). These data indicate that the α-Hydroxytropolone and N-Hydroxypyridinedione chemotypes should be investigated in the future to determine their mechanism(s) of action allowing further development as therapeutics for RVFV and LACV, and these chemotypes should be evaluated for activity against related pathogens, including Hantaan virus, severe fever with thrombocytopenia syndrome virus, Crimean-Congo hemorrhagic fever virus.
TBDMS (t-BuMe2Si, t-butyldimethylsilyl) ethers of a variety of phenols have been deprotected with KHF2 in MeOH, at room temperature. Carboxylic ester and labile phenolic acetate were unaffected under these conditions. In competition reactions between TBDMS ethers of a phenol and two primary benzylic alcohols, the phenolic ether underwent cleavage whereas the alcohol ethers remained intact. From a substrate containing both a phenolic hydroxyl group and a secondary, doubly benzylic hydroxyl group protected as TBDMS ethers, the phenol was rapidly and selectively released. Cleavage of TBDMS, TBDPS, and TIPS ethers of a phenol was also compared. TBDMS and TBDPS ethers underwent cleavage at room temperature within 30 min, whereas removal of the TIPS ether required 2.5 hours. Ease of cleavage appears to be TBDMS ≈ TBDPS > TIPS. At 60 °C, TBDMS ethers of primary benzylic, allylic, and unactivated alcohols can be efficiently desilylated over a prolonged period (13–17 h). Thus, KHF2 proves to be a mild and effective reagent for the selective desilylation of phenol TBDMS ethers at room temperature.
Rift Valley Fever Virus (RVFV) is a veterinary and human pathogen and is an agent of bioterrorism concern. Currently, RVFV treatment is limited to supportive care, so new drugs to control RVFV infection are urgently needed. RVFV is a member of the Bunyavirales order, and replication of these viruses depends on the viral endonuclease activity of the viral L protein. Screening for RVFV replication inhibitors among compounds with divalent cation-coordinating motifs similar to known viral nuclease inhibitors identified 31 novel RVFV inhibitors with selective indexes from 5 – 402 and 50% effective concentrations of 0.54 – 56 µM in Vero cells, primarily α-Hydroxytropolones and N-Hydroxypyridinediones. Inhibitor activity and selective index was validated in the human cell line A549. To evaluate specificity, select compounds were tested against another Bunyavirus, La Crosse Virus (LACV). Conservation of the enzymatic activity such as the cap-snatching mechanism among the Bunyavirales implies that the α-Hydroxytropolone and N-Hydroxypyridinedione chemotypes hold potential for development into treatments for related pathogens, including Hantaan Virus, Severe fever with thrombocytopenia syndrome virus, Crimean-Congo Hemorrhagic Fever Virus, and LACV. Keywords: Rift Valley Fever Virus 1, La Crosse virus 2, Cap-snatching endonuclease 3, Replication inhibitors 4, α-Hydroxytropolones 5, N-Hydroxypyridinediones 6.
Oxidopyrylium ylides are versatile and reactive species that have been used widely in total synthesis, particularly due to their ability to undergo complexity‐forming [5+2] cycloaddition reactions. Group transfer strategies have been generally limited to intramolecular cycloaddition reactions, however, likely due to the short lifetime of the active ylide. However, in 1992 Wender and Mascarenas found that this limitation can be overcome through the use of methyl triflate based pre‐ylide salt. This article describes the procedure for synthesis of 5‐Hydroxy‐4‐methoxy‐2‐methylpyrylium trifluoromethanesulfonate from Kojic acid. It presents some of the important points to be considered, the conditions that need to be maintained, characterization data, and the reagents required, as well as the techniques used and the equipment setup that are vital to carrying out the process. The article also describes the hazards associated with working with chemicals and the ways to deal with these hazards.
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