Troponoids Can Inhibit Growth of the Human Fungal Pathogen Cryptococcus neoformans

Abstract

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 M. We screened compounds with MICs of Յ20 M for cytotoxicity in liver hepatoma cells. Fifty percent cytotoxicity values (CC 50 s) ranged from 4 to Ͼ100 M. The therapeutic indexes (TI, CC 50 /MIC) for most of the troponoids were fairly low, with most being Ͻ8. However, two compounds had TI values that were Ͼ8, including a tropone with a TI of Ͼ300. 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.

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

“…2). Lactonization of #107 to 280 was reported by our labs previously, and was found to take place under fairly mild conditions (0.05% trifluoroacetic acid in water/acetonitrile) (Donlin et al, 2017). Here, we suggest that this lactonization (between #107 to 280) may take place in cell cultures.…”

“…Compounds #106–120, 143–147, 273–274, and 335 were synthetized from kojic acid as previously described (D'Erasmo et al, 2016; Hirsch et al, 2014; Ireland et al, 2016; Meck et al, 2012; Williams et al, 2013). Compounds #280, 308–313, 315, and 317–319 were synthesized as described (Donlin et al, 2017). Compounds #261–264 were made using the Banwell method (Banwell et al, 1991).…”

Biosynthesis of Tropolones in Streptomyces spp.: Interweaving Biosynthesis and Degradation of Phenylacetic Acid and Hydroxylations on the Tropone Ring

“…The contiguous array of at least three oxygen atoms (ketone/hydroxyl) and the sevenmembered aromatic ring are both essential for the broad bioactivities of compound 1 (6,7). Interest in the potential bioactivities and unusual structure of compound 1 has generated a number of chemical synthesis studies focused on the derivatization of tropolone, as well as studies supporting tropolone as a very promising therapeutic drug lead (2,(8)(9)(10).…”

Identification of 4-isopropyl–thiotropolone as a novel anti-microbial: regioselective synthesis, NMR characterization, and biological evaluation

“…The tropone ring has a unique structure and properties and despite their non-benzenoid nature, they are planar and possess aromatic character. Natural and synthetic compounds that have the troponoid core have profound biological activities and have been used as antitumor, [1][2][3] antifungal, 4 and antimicrobial agents. 5 The biological activities of these compounds has been mainly attributed to their inhibitory effect on bimetallic enzymes.…”

“…14,15 This antibiotic was found to exhibit antibacterial, antifungal, and antiprotozoal activities in vitro. Recently, Donlin and coworkers 4 reported that thiotropolone 5 can inhibit the growth of the fungus Cryptococcus neoformans with a minimal 80% inhibitory concentration (MIC 80 ) of 0.25 mM. In our effort to design and synthesize new thiotropolones to treat pathogenic fungi and multidrug resistant bacteria, we used the natural product b-thujaplicin (2) as starting point (Fig.…”