Antimycotic Activity and Acute Toxicity of Benzopyranopyrans and Related Compounds

Abstract

A series of 39 new benzopyranopyrans and related compounds were synthesised and their antimycotic activity in vitro was evaluated against 4 species of human pathogenic yeasts which were insensitive to miconazole, isoconazole and tolnaftate. The minimum inhibitory concentrations (MICs) of these commercial compounds ranged between 50 and 150 µg/ml. Of the new compounds, 15 were active against 5 strains of Cryptococcus neoformans, while 9 more were active against 3 of these strains with an MIC of 6 µg/ml or lower. Similar MICs were shown by 5 compounds which were active against Candida albicans and 3 which were active against Trichosporon cutaneum. All the active compounds were found to be less toxic than the 3 commercial antimycotics, as judged by their LD₅₀ values in mice. A number of deductions were made regarding the structural variations which resulted in the heterogeneity of response shown by the strains of C. neoformans tested in this series.

The in vitro Antimycotic Activity and Acute Toxicity of Third-Generation Bezylidenetetralones and Heteroarylidenetetralones

“…Nineteen members of this third generation of E-2-benzylidene-1-tetralones (table 1) were synthesised under the new strong acid and base reaction conditions as we intended to introduce heteroaromatic compounds (13)(14)(15)(16)(17)(18)(19), polychlorinated (9-11), ionisable hydroxyl sulphonic and acidic groups [2,4,7] as well as new ether, ester (1, 3, 5, 6) and cyano (12) residues as substituents for comparison to the first and second generation 1-4 and 14 E-2-benzylidene-1-tetralones, respectively. The broad spectrum of antimycotic activity exhibited by 10 of the new compounds (table 3) was generally dependent on the presence of free or ionisable acidic-oxygenated functional groups (2, 4, 7) or nitrogenous residues having free or nonmethylated nitrogen atoms, and specifically when the nitrogen substituent was a 6-membered ring (pyridyl derivatives; 14, 16, 17) and, to a lesser extent, when the nitrogen residue was that of a 5-membered pyrrole ring (19).…”

“…Although the simple E-2-benzylidine-1-tetralones (1-12) were overall less toxic than those where the phenyl group was replaced with a heterocyclic moiety (13)(14)(15)(16)(17)(18)(19), as reflected by their LD 50 values in mice, many were comparably or slightly more toxic than the least toxic commercial agent, amphotericin B. When compared to the most active of the commercial agents, sertaconazole, the in vivo toxicity of the new compounds was found to be marginally better.…”

“…The toxicities of the new compounds and the references compounds listed above were determined in vitro in cultured HeLa cells (Ohio) and in a HeLa growth medium [14,15] in triplicate sets at each concentration over a concentration range of 1-500 Ìg/ml per culture bottle. The cells in each culture bottle were harvested and counted using a haemocytometer.…”

“…The in vivo toxicity of the compounds 1-19 compared to the 6 commercial agents was assessed in triplicate sets of 10 MFI mice using an acute toxicity procedure [9,15]. The LD 50 values were considered valid for any group of mice, per compound or agent, when the survival coefficient of variance for the particular dose used was within 3-5% [6,9].…”

Benzylideneindanones and Benzylidenebenzosuberones: Relationship between Structure, Antimycotic Activity and Acute Toxicity

“…Other wise, the results were rejected and the experiment repeated [6,13], All the mice used in the LD50 experi ments were examined at the time of injection for any discomfort at the site of injection, and those that seemed to be in pain were killed as a general proce dure. All mice were autopsied and their internal organs examined for any organ discolouration or variation in texture and size from anatomical norm [6], All surviv ing mice within a set were killed 4 weeks after the start of any experiment [14]. Table 1 shows the different groups and substitution patterns in the two series of the compounds synthesized, the benzylideneindanones ( 1-12) and benzylidencbenzosuberones (13-24).…”