Studies on the Configurational Stability of Tropolone-Ketone-, Ester-, and Aldehyde-Based Chiral Axes.

Recent studies have revealed that tropolone-amide aryl C-C(O) rotational barriers are dramatically higher than those of analogous benzamide-based systems, and as a result, they have an increased likelihood of displaying high configurational stability. Studies on other tropolone-based chiral axes are important to assess the generality of this phenomenon. Herein, we describe a series of studies on the rotational barriers of tropolone-ketone, tropolone-ester, and tropolone-aldehyde chiral axes. These studies are complemented with computational modeling of the dynamics of these and analogous benzenoid variants to illuminate the impact that tropolone may have on aryl-C(O) configurational stability.

Metal coordinating inhibitors of Rift Valley fever virus replication.

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.

Divergent synthesis of a thiolate-based α-hydroxytropolone library with a dynamic bioactivity profile.

Here we describe a rapid and divergent synthetic route toward structurally novel αHTs functionalized with either one or two thioether or sulfonyl appendages. Evaluation of this library against hepatitis B and herpes simplex virus, as well as the pathogenic fungus Cryptococcus neoformans, and a human hepatoblastoma (HepDES19) revealed complementary biological profiles and new lead compounds with sub-micromolar activity against each pathogen.

KHF2, a mild and selective desilylating agent for phenol t-butyldimethylsilyl (TBDMS) ethers.

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.

Efficacy and cytotoxicity in cell culture of novel α-hydroxytropolone inhibitors of hepatitis B virus ribonuclease H.

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.