Structure-Antifungal Activity Relationships in Substituted Butenolides

Within the framework of this Thesis, several series of 3-(4-bromophenyl)-2,5- -dihydrofuran-2-ones with various substituents at C(5) derived from in vitro antifungally active 3-(4-bromophenyl)-5-acetyloxymethyl-2,5-dihydrofuran-2-one were prepared with the aim of further development of potential antifungals based on this lead. Primarily, we focused on the synthesis of furanones bearing alkylidene or alkoxymethyl/aryloxymethyl moiety in position 5. We found that 5-acyloxymethyl and 5-aryloxymethyl furanone derivatives undergo elimination leading to 3-(4-bromophenyl)-5-methylene-2,5-dihydrofuran-2-one under the antifungal screening conditions. This compound initiates fungal cell membrane disruption and is responsible for the antifungal activity of the former. The 5-alkoxymethyl analogues are unable to undergo the elimination process and are therefore inactive. The antifungal activity of 5- alkylidene furanones depends on the substitution of alkylidene side chain. Some of the target compounds displayed interesting cytostatic activities against HeLa S3 and CCRF-CEM cells (IC50 < 5 µmol.L-1 ). Furthermore, syntheses of 4-substituted or 4,5-disubstituted-3-(4-bromophenyl)-2,5- -dihydrofuran-2-ones were carried out. Some of the prepared derivatives possessed notable antifungal or antimicrobial activity