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

Abstract

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.

Characterization of lipophilicity and antiproliferative activity of E-2-arylmethylene-1-tetralones and their heteroanalogues

“…Numerous biological activity have been attributed to the tetralones mentioned. So, we have reported the synthesis and antifungal properties of some bicyclic ␣,␤-unsaturated ketones-homoisoflavones-as E-2-arylmethylene-1-tetralones, E-3-arylmethylenechroman-4-ones, E-3-arylmethylene-1-thiochroman-4-ones [11,12]. Several representants of these classes of compounds showed remarkable antifungal activity.…”

Analysis of vibrational spectra of some new E- and Z-4-arylidene-3-isochromanones

“…For instance, oosponol (1-isochromanone derivative, isocoumarin), a fungal metabolite, displays antifungal effects [1,2]; fusarubine, an antibiotic of isochromane skeleton, shows antibacterial, antifungal, insecticide and phytotoxic effects [3]. A previous work [4] done in one of the contributing laboratories focused on the study of cyclic a,h-unsaturated ketones (homoisoflavones) such as (E)-2-(arylmethylene)-1-tetralones, (E)-3-(arylmethylene)-4-chromanones and (E)-3-(arylmethylene)-1-thiochroman-4-ones that were screened against human pathogenic yeasts (Cryptococcus neoformans and Candida spp.). Recently, we have extended this research with studies of a series of isomeric 4-(arylmethylene)-3-isochromanones.…”

Lipophilicity and antiproliferative activity profiling of 2-benzylidencycloalkanones

“…The Zconfiguration, however, is highly unfavourable (strong steric interaction between the aryl and carbonyl groups) [26]. In accordance with this, the E-configuration unambiguously was verified by the appearance of the "diagnostic" H-2a (H-␣) proton signal in the appropriate range (7.4-7.8 ppm) in the 1 H NMR spectra [12]. The 1 H and 13 C assignments of the compounds were based on simple 1 H and 13 C measurements and corroborated by 1 H-1 H COSY, gradient enhanced 13 C-1 H HSQC as well as 13 C-1 H HMBC experiments executed using standard Varian software.…”

“…Several representatives of these classes of compounds showed remarkable antiproliferative and cytotoxic effect-in a cytotoxicity screening against A431 human adenocarcinoma cells. Additional biological effects have been reported also and described previously elsewhere [12][13][14][15].…”