Search

α-Hydroxytropolones (αHTs) have potent antiviral activity against herpes simplex virus-1 and -2 (HSV-1 and HSV-2) in cell culture, including against acyclovir-resistant mutants, and as a result have the potential to be developed as antiviral drugs targeting these viruses. We recently described a convenient final-step amidation strategy to their synthesis, and this was used to generate 57 amide-substituted αHTs that were tested against hepatitis B virus. The following manuscript describes the evaluation of this library against HSV-1, as well as a subset against HSV-2. The structure-function analysis obtained from these studies demonstrates the importance of lipophilicity and rigidity to αHT-based anti-HSV potency, consistent with our prior work on smaller libraries. We used this information to synthesize and test a targeted library of 4 additional amide-appended αHTs. The most potent of this new series had a 50% effective concentration (EC 50 ) for viral inhibition of 72 nM, on par with the most potent αHT antivirals we have found to date. Given the ease of synthesis of amide-appended αHTs, this new class of antiviral compounds and the chemistry to make them should be highly valuable in future anti-HSV drug development., Competing Interests: LAM and RPM are inventors on patents describing the HSV antiviral activity of αHTs., (This journal is © The Royal Society of Chemistry.)

Tropone is the prototypical aromatic 7-membered ring, and can be found in virtually any undergraduate textbook as a key example of non-benzenoid aromaticity. Aside from this important historical role, tropone is also of high interest as a uniquely reactive synthon in complex chemical synthesis as well as a valuable chemotype in drug design. More recently, there has been growing interest in the utility of tropones for catalysis and material science. Thus, synthetic strategies capable of synthesizing functional tropones are key to fully exploiting the potential of this aromatic ring system. Cycloaddition reactions are particularly powerful methods for constructing carbocycles, and these strategies in turn have proven to be powerful for generating troponoids. The following review article provides an overview of strategies for troponoids wherein the 7-membered carbocycle is generated through a cycloaddition reaction. Representative examples of each strategy are also provided.

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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests:pending patent application. AP, GZ, JB, JT, and RM are inventors on a pending US patent application covering use of these compounds to treat Bunyavirus infections. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Herein, we describe the formation of tropolones through the autoxidation of Büchner reaction-derived cycloheptatrienes. The reaction is exceptionally simple procedurally, as it involves blowing a stream of compressed air over the cycloheptatriene, and the products can be obtained without any need for chromatography. The chemistry works specifically on dioxolane-fused systems or close variants, and substitution patterns are also important. A radical-based mechanistic hypothesis is put forward to explain these results. Finally, we demonstrate the utility of the overall process in the synthesis of amide-appended tropolones and an isomer of stipitatic acid.

The Hepatitis B Virus (HBV) ribonuclease H (RNaseH) is a promising but unexploited drug target. Here, we synthesized and analyzed a library of 57 amide-containing α-hydroxytropolones (αHTs) as potential leads for HBV drug development. Fifty percent effective concentrations ranged from 0.31 to 54 μM, with selectivity indexes in cell culture of up to 80. Activity against the HBV RNaseH was confirmed in semi-quantitative enzymatic assays with recombinant HBV RNaseH. The compounds were overall poorly active against human ribonuclease H1, with 50% inhibitory concentrations of 5.1 to >1,000 μM. The αHTs had modest activity against growth of the fungal pathogen Cryptococcus neoformans, but had very limited activity against growth of the Gram - bacterium Escherichia coli and the Gram + bacterium Staphylococcus aureus, indicating substantial selectivity for HBV. A molecular model of the HBV RNaseH templated against the Ty3 RNaseH was generated. Docking the compounds to the RNaseH revealed the anticipated binding pose with the divalent cation coordinating motif on the compounds chelating the two Mn ++ ions modeled into the active site. These studies reveal that that amide αHTs can be strong, specific HBV inhibitors that merit further assessment toward becoming anti-HBV drugs., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We previously reported that troponoid compounds profoundly inhibit replication of herpes simplex virus (HSV)-1 and HSV-2 in cell culture, including acyclovir-resistant mutants. Synthesis of 26 alpha-hydroxylated tropolones (αHTs) led to a preliminary structure-activity relationship highlighting the potency of bi-phenyl side chains. Here, we explore the structure-activity relationship in more detail, with a focus on various biaryl and other lipophilic molecules. Along with our prior structure-function analysis, we present a refined structure-activity relationship that reveals the importance of the lipophilicity and nature of the side chain for potent anti-HSV-1 activity in cells. We expect this new information will help guide future optimization of αHTs as HSV antivirals.

α-Hydroxytropolones (αHTs) are excellent metalloenzyme-inhibiting fragments that have been the basis for the development of potent inhibitors of various therapeutically important enzymes. The following manuscript describes a final-step amidation approach for αHT diversification. The method takes advantage of a scalable, chromatography-free synthesis of a carboxylic acid-appended αHT, and in the present manuscript we describe the synthesis of eight amide-containing αHTs, three of which we envision using as chemical probes. We expect that the general strategy will find widespread usage in both chemical biology and medicinal chemistry studies on αHTs.

3,7-Dihydroxytropolones (3,7-dHTs) are highly oxygenated troponoids that have been identified as lead compounds for several human diseases. To date, structure-function studies on these molecules have been limited due to a scarcity of synthetic methods for their preparation. New synthetic strategies towards structurally novel 3,7-dHTs would be valuable in further studying their therapeutic potential. Here we describe the successful adaptation of a [5 + 2] oxidopyrilium cycloaddition/ring-opening for 3,7-dHT synthesis, which we apply in the synthesis of a plausible biosynthetic intermediate to the natural products puberulic and puberulonic acid. We have also tested these new compounds in several biological assays related to human immunodeficiency virus (HIV), hepatitis B virus (HBV) and herpes simplex virus (HSV) in order to gain insight into structure-functional analysis related to antiviral troponoid development.

Cryptococcus neoformans is a pathogen that is common in immunosuppressed patients. It can be treated with amphotericin B and fluconazole, but the mortality rate remains 15 to 30%. Thus, novel and more effective anticryptococcal therapies are needed. The troponoids are based on natural products isolated from western red cedar, and have a broad range of antimicrobial activities. Extracts of western red cedar inhibit the growth of several fungal species, but neither western red cedar extracts nor troponoid derivatives have been tested against C. neoformans We screened 56 troponoids for their ability to inhibit C. neoformans growth and to assess whether they may be attractive candidates for development into anticryptococcal drugs. We determined MICs at which the compounds inhibited 80% of cryptococcal growth relative to vehicle-treated controls and identified 12 compounds with MICs ranging from 0.2 to 15 μM. We screened compounds with MICs of ≤20 μM for cytotoxicity in liver hepatoma cells. Fifty percent cytotoxicity values (CC 50 s) ranged from 4 to >100 μM. The therapeutic indexes (TI, CC 50 /MIC) for most of the troponoids were fairly low, with most being <8. However, two compounds had TI values that were >8, including a tropone with a TI of >300. These tropones are fungicidal and are not antagonistic when used in combination with fluconazole or amphotericin B. Inhibition by these two tropones remains unchanged under conditions favoring cryptococcal capsule formation. These data support the hypothesis that troponoids may be a productive scaffold for the development of novel anticryptococcal therapies., (Copyright © 2017 American Society for Microbiology.)