Antifungal 3,5-disubstituted furanones: From 5-acyloxymethyl to 5-alkylidene derivatives.
5-Acetoxymethyl-3-(4-bromophenyl)-2,5-dihydrofuran-2-one previously described as highly antifungally active was found to provide the corresponding 5-methylene derivative via an unusual DMSO-promoted elimination of the ester group at C5 under antifungal assay conditions. Since the latter possessed nearly the same antifungal effect as that originally reported for the former, the 5-acetoxymethyl furanone just served as a precursor of the actual antifungally active species. A few series of compounds with alkyloxy, aryloxy and alkylidene substituents at C5 of the parent furanone structure were therefore prepared and evaluated. In line with the ease of elimination of the substituent from C5, low activities of the 5-alkoxy compounds were observed. On the other hand, their 5-aryloxymethyl congeners were found to be capable of liberating the antifungally active 5-methylene furanone into the testing medium. The antifungal effect of the 5-alkylidene derivatives was highly sensitive to substitution of the alkylidene moiety; a substituent in the allylic position was necessary for a compound to retain high activity. Parallel evaluation of cytostatic activity showed moderate activities of the antifungally active derivatives against HeLa S3 and CCRF-CEM lines. Cell cycle analysis of CCRF-CEM cells following the treatment with 5-methylene-3-(4-bromophenyl)-2,5-dihydrofuran-2-one revealed that this compound is a necrotic agent.
Centre for New Antivirals and Antineoplastics, Department of Inorganic and Organic Chemistry, Charles University, Faculty of Pharmacy, Heyrovského 1203, CZ-500 03 Hradec Králové, Czech Republic.
Petr
P
Senel
Lucie
L
Tichotová
Ivan
I
Votruba
Vladimír
V
Buchta
Marcel
M
Spulák
Jirí
J
Kunes
Milan
M
Nobilis
Ondrej
O
Krenk
Milan
M
Pour
D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis; D002460:Cell Line; D054697:Cytostatic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests
D000935:Antifungal Agents; D054697:Cytostatic Agents; D005663:Furans; C039281:furan