Objectives: A new series of E-2-arylmethylene-1-tetralones and E-2-heteroarylmethylene-1-tetralones (third generation) were designed as potential antimycotic agents against human pathogenic yeasts. Methods: The new compounds were obtained by aldol condensation of 1-tetralone with the appropriately substituted aldehydes in either acid- or base-catalysed conditions. These compounds were tested for their in vitro antimycotic activity against 24 strains of Cryptococcus neoformans, Candida spp. and Trichosporon cutaneum by a microtitre well technique in a liquid casitone medium, using a double dilution method. The toxicity of the new compounds was determined in vitro in cultured HeLa cells, in HeLa growth medium and in vivo in MFI mice. Results: Nineteen new E-2-benzylidine-1-tetralones were prepared, and 16 of the tested compounds showed superior antimycotic activity when compared to the first-generation E-2-benzylidine-1-tetralones synthesised previously. Twelve of these third-generation compounds were more active against different strains of yeasts than 6 commercial antimycotic agents similarly tested. An in vitro toxicity study and an in vivo acute toxicity study in MFI mice showed that these compounds were severalfold less toxic than most of the commerical antimycotics, with 4 being comparable to or less toxic than the least toxic of the commercial agents (amphotericin B) tested by the same procedures. Conclusions: Twelve members of this new E-2-benzylidine-1-tetralone class of compounds are promising candidates for antimycotic agents worthy of further investigation.

Fifty-five new compounds belonging to the naturally occurring benzylidenechromanones were synthesised and their activity against the important human pathogenic yeasts Cryptococcus neoformans, Candida spp., Trichosporon cutaneum and Torulopsis glabrata was assessed in vitro using a microtitre technique. These yeasts had already been found resistant to miconazole, at a minimum inhibitory concentration (MIC) of 100 µg/ml or more. The structural differences between the molecules of the new compounds, such as their three-dimensional shape, the presence of oxygen or sulphur hetero-atoms, or a cyclic bridge, were studied to establish models for their structure-to-antimycotic activity. Twenty-eight of the compounds were found active against the tested yeasts and had an MIC of 6 µg/ml. There was a heterogeneity in the response of the yeasts to the active compounds, which could be linked to structural factors in C. neoformans.

A series of new compounds were evaluated for acute in vivo toxicity. Their synthesis and antifungal activity have previously been described by us. The naturally occurring class of compounds to which they belong - the benzylidenechroman-4-ones - have been identified as a potential source of new antifungal agents. These compounds were found to be less toxic, as judged by acute toxicity, than existing commercially available antifungals. A number of conclusions can be drawn about the relationship of structural changes in this series of compounds to increases or decreases in acute toxicity.

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A series of E-2-benzylidene-1-indanones and E-2-benzylidene-1-benzosuberones were synthesized to investigate their in vitro antifungal activity against 24 strains belonging to important human pathogenic yeasts, such as Cryptococcus neoformans, Candida spp. and Trichosporon cutaneum. These strains were shown to be resistant to miconazole and isoconazole. There was a diversity in response among the different strains. Many of the compounds tested were shown to have good activity and many had minimum inhibitory concentrations (MICs) of 6 µg/ml or lower against most of the strains. The standard systemic and topical commercial drugs also showed a great degree of diversity, exhibiting MICs that ranged from 6 to > 100 µg/ml against the same yeast strains. The in vivo toxicity of the synthesized compounds tested by an acute toxicity procedure in mice (MFI strain) and the in vitro activity in HeLa cells suggests that most of the active compounds were of lower toxicity, while only a few were of a toxicity similar to that of the least toxic commercial antifungal agent investigated in our animal and cell culture models (amphotericin B). The relatively low LD₅₀ and good MIC values of most of our compounds in comparison to the least toxic and most active commercial agents tested (amphotericin B and haloprogin, respectively) justifies the testing of these synthetic agents for further development.