Diversity-Oriented Synthesis of Highly Fluorescent Fused Isoquinolines for Specific Subcellular Localization.

A multicomponent diversity-oriented synthesis of new highly emissive tetracyclic isoquinolines that target specific organelles is described. The title compounds were prepared via a three-step protocol starting with an Ugi four-component reaction, followed by either an intramolecular alkyne hydroarylation and subsequent alkene isomerization or through a Pomeranz-Fritsch-type cyclization with a final intramolecular Heck reaction. Subcellular localization studies of these compounds using green channel confocal microscopy revealed remarkable and distinctive distribution patterns in live cells, showing an unprecedented high selectivity and imaging contrast. The differentiated organelle visualization-including localizers for mitochondria, lysosomes, Golgi apparatus, endoplasmic reticulum, and plasma membrane-was achieved by varying the nature of the tetracyclic system and substituent pattern, changing the original four-component set in the starting Ugi reaction.

Synthesis and antifungal activity of novel oxazolidin-2-one-linked 1,2,3-triazole derivatives.

Novel oxazolidin-2-one-linked 1,2,3-triazole derivatives (4a-k) were synthesized by straightforward and versatile azide-enolate (3 + 2) cycloaddition. The series of compounds was screened for antifungal activity against four filamentous fungi as well as six yeast species of Candida spp. According to their efficiency and breadth of scope, they can be ordered as 4k > 4d > 4h > 4a, especially in relation to the activity displayed against Candida glabrata ATCC-34138, Trichosporon cutaneum ATCC-28592 and Mucor hiemalis ATCC-8690, i.e. compounds 4d, 4h and 4k showed excellent activity against C. glabrata (MIC 0.12, 0.25 and 0.12 µg mL-1, respectively), better than that of itraconazole (MIC 1 µg ml-1). The activity of compound 4d (MIC = 2 µg mL-1) was higher than that observed for the standard antifungal drug (MIC = 8 µg mL-1) against Trichosporon cutaneum, while compound 4k displayed an excellent antimycotic activity against Mucor hiemalis (MIC = 2 µg mL-1vs. 4 µg mL-1 for itraconazole). In addition, we describe herein a novel mild and eco-friendly synthetic protocol for obtaining ß-ketosulfones (adducts to afford compounds 4a-k) from α-brominated carbonyls in an aqueous nanomicellar medium at room temperature.

Antifungal activity of 1'-homo-N-1,2,3-triazol-bicyclic carbonucleosides: A novel type of compound afforded by azide-enolate (3+2) cycloaddition.

The first report of 1'-homo-N-1,2,3-triazol-bicyclic carbonucleosides (7a and 7b) is described herein. Azide-enolate (3+2) cycloaddition afforded the synthesis of this novel type of compound. Antifungal activity was evaluated in vitro against four filamentous fungi (Aspergillus fumigatus, Trichosporon cutaneum, Rhizopus oryzae and Mucor hiemalis) as well as nine species of Candida spp. as yeast specimens. These pre-clinical studies suggest that compounds 7a and 7b are promising candidates for complementary biological studies due to their good activity against Candida spp.

Azide-enolate 1,3-dipolar cycloaddition in the synthesis of novel triazole-based miconazole analogues as promising antifungal agents.

Seven miconazole analogs involving 1,4,5-tri and 1,5-disubstituted triazole moieties were synthesized by azide-enolate 1,3-dipolar cycloaddition. The antifungal activity of these compounds was evaluated in vitro against four filamentous fungi, including Aspergillus fumigatus, Trichosporon cutaneum, Rhizopus oryzae, and Mucor hiemalis as well as three species of Candida spp. as yeast specimens. These pre-clinical studies suggest that compounds 4b, 4d and 7b can be considered as drug candidates for future complementary biological studies due to their good/excellent antifungal activities.

A facile synthesis of novel miconazole analogues and the evaluation of their antifungal activity.

Four novel miconazole analogues (8-11) were synthetized and evaluated for activity against four filamentous fungi (Mucor hiemalis, Aspergillus fumigatus, Trichosporon cutaneum, and Rhizopus oryzae) and eight species of Candida as yeast specimens. Compounds 9 and 10 showed very good activity when evaluated in yeast (MIC 0.112 and 0.163 µg/mL) compared to the reference compound, itraconazole (MIC 0.067 µg/mL). The best antifungal activity in filamentous strains was shown by compound 9. Hence compounds 9 and 10 represent new leads for further pharmacomodulation in this series.