No abstract

3-(Substituted phenyl)-5-acyloxymethyl-2H,5H-furan-2-ones related to the natural product (-)incrustoporine were synthesized and their in vitro antifungal activity evaluated. The compounds with halogen substituents on the phenyl ring displayed much higher antifungal effect against Aspergillus fumigatus than selected representatives of azole antifungal drugs. In particular, the activity (1.34 microg/mL) of the most promising derivative, 3-(3,4-dichlorophenyl)-5-pivaloyloxymethyl-2H,5H-furan-2-one, was comparable to that of amphotericin B (0.5 microg/mL). Preliminary evaluation of the toxicity of the compound was carried out as well. Considering the size and properties of these molecules in comparison with those of amphotericin B, further development of this novel group of antifungals may lead to substances with better pharmacological profiles than that of the standard anti-Aspergillus drug.

A set of 40 derivatives of 3-hydroxypicolinic acid and 2-sulfanylbenzoic acid, isosteric to salicylanilides was synthesized. The compounds were evaluated for in vitro activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium, Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata, Trichosporon beigelii, Aspergillus fumigatus, Absidia corymbifera, Trichophyton mentagrophytes and Microsporum gypseum. Structure-activity relationships of antimycobacterial activity and antifungal activity against T. mentagrophytes and M. gypseum were analyzed by the Free-Wilson method. An increase in antimycobacterial activity was observed only for the sulfanylbenzoic acid derivatives, especially those with the benzyl moiety. The antifungal activity was not significant.

Three 3-(halogenated phenyl)-5-acyloxymethyl-2,5-dihydrofuran-2-ones were evaluated for activity against 191 strains of common and emerging yeasts and Aspergillus species by the broth microdilution test performed according to NCCLS guidelines. The furanone derivatives displayed broad-spectrum in vitro activity against potentially pathogenic yeasts and molds, especially Aspergillus spp. (MIC < 2.0 g/ml) and fluconazoleresistant yeast isolates, including Candida glabrata and Saccharomyces cerevisiae. The 4-bromophenyl derivative was the most effective derivative against the majority of species tested, except for the Candida tropicalis and C. glabrata strains, which were more susceptible to the 3-chlorophenyl derivative. The 3,4-dichlorophenyl derivative possessed a lesser in vitro antifungal effect. The potential of further experiments on animal infection and clinical studies is supported by the relatively low cytotoxicity and acute toxicity of the 4-bromophenyl compound. Thus, the halogenated 3-phenyl-5-acyloxymethyl derivatives of 2,5-dihydrofuran-2-one represent a novel, promising group of compounds with significant activity against relevant opportunistic fungi that are pathogenic to humans.The incidence of and mortality due to fungal infections have increased over the past few decades, particularly in the setting of immunocompromised hosts. In spite of the introduction of several new antifungal drugs, such as caspofungin and voriconazole, the therapeutic management of serious invasive mycoses still remains a challenge for pharmaceutical research and industry (11).3-(Halogenated phenyl)-5-acyloxymethyl-2,5-dihydrofuranones (Fig. 1A) represent a novel class of butenolide antimycotics based on (Ϫ)incrustoporin (the minus sign means that the compound is a levorotatory enantiomer), obtained from the extract of fermentation of the basidiomycete Incrustoporia carneola, as the lead structure. The natural product displays an antifungal effect toward phytopathogenic molds and some cytotoxic activity ( Fig. 1) (15). In agreement with these findings, our antifungal testing revealed that the racemic form of the natural product exhibited only a marginal effect (MIC Ͼ 32 g/ml) on our set of yeast and mold isolates (12). The preparation of synthetic derivatives with halogenated phenyl at C-3 and a methyl group at C-5 led to a significant increase of the in vitro antifungal effect, especially in filamentous fungi (12,13,14). The highest in vitro antifungal activity was linked to the substitution of the phenyl group at C-3 by halogens at positions 3 and 4 and to the presence of an acyloxymethyl group at C-5 (13). The conversion of 5-hydroxymethyl derivatives into esters resulted in a broader spectrum of activity and in MICs below 4 g/ml for most yeasts and molds tested. Interestingly, the effect was not stereospecific, i.e., there were no significant differences in the MICs of the enantiomers and the racemate (13).Based on these experiments, we decided to investigate the in vitro profile of the most promising three esters (LNO6...

A series of 81 3-phenyl-2H-benzoxazine-2,4(3H)-diones with substitution at C(6) on the benzoxazine ring and on the phenyl moiety was synthesized; the compounds were evaluated for antifungal activity against five strains of potentially pathogenic fungi (Absidia corymbifera, Aspergillus fumigatus, Candida albicans, Microsporum gypseum and Trichophyton mentagrophytes). Structure-activity relationships against T. mentagrophytes and M. gypseum were determined using the Free-Wilson method, which was further combined with the approach of Hansch. In vitro antifungal activity becomes higher with increasing electron-accepting ability of the substituents on the phenyl ring, and with increasing lipophilicity.