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Impact of Absolute Stereochemistry on the Antiangiogenic and Antifungal Activities of Itraconazole.

ABSTRACT: Itraconazole is used clinically as an antifungal agent and has recently been shown to possess antiangiogenic acitivity. Itraconazole has three chiral centers that give rise to eight stereoisomers. The complete role of stereochemistry in the two activities of itraconazole, however, has not been addressed adequately. For the first time, all eight stereoisomers of itraconazole (1a-1h) have been synthesized and evaluated for activity against human endothelial cell proliferation and for antifungal activity against five fungal strains. Distinct antiangiogenic and antifungal activity profiles of the trans- stereoisomers, especially 1e and 1f, suggest different molecular mechanisms underlying the anti-angiogenic and anti-fungal activities of itraconazole.

SUBMITTER: Shi W

PROVIDER: S-EPMC3165044 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Synthesis, Absolute Configuration, Antibacterial, and Antifungal Activities of Novel Benzofuryl β-Amino Alcohols.

Project description:A series of new benzofuryl α-azole ketones was synthesized and reduced by asymmetric transfer hydrogenation (ATH). Novel benzofuryl β-amino alcohols bearing an imidazolyl and triazolyl substituents were obtained with excellent enantioselectivity (96-99%). The absolute configuration (R) of the products was confirmed by means of electronic circular dichroism (ECD) spectroscopy supported by theoretical calculations. Selected benzofuryl α-azole ketones were also successfully asymmetrically bioreduced by fungi of Saccharomyces cerevisiae and Aureobasidium pullulans species. Racemic and chiral β-amino alcohols, as well as benzofuryl α-amino and α-bromo ketones were evaluated for their antibacterial and antifungal activities. From among the synthesized β-amino alcohols, the highest antimicrobial activity was found for (R)-1-(3,5-dimethylbenzofuran-2-yl)-2-(1H-imidazol-1-yl)ethan-1-ol against S. aureus ATCC 25923 (MIC = 64, MBC = 96 μg mL-1) and (R)-1-(3,5-dimethylbenzofuran-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-ol against yeasts of M. furfur DSM 6170 (MIC = MBC = 64 μg mL-1). In turn, from among the tested ketones, 1-(benzofuran-2-yl)-2-bromoethanones (1-4) were found to be the most active against M. furfur DSM 6170 (MIC = MBC = 1.5 μg mL-1) (MIC-minimal inhibitory concentration, MBC-minimal biocidal concentration).

| S-EPMC7560283 | biostudies-literature

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Project description:Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disabling disease that can cause long-term severe arthritis. Since the last large CHIKV outbreak in 2015, the reemergence of the virus represents a serious public health concern. The morbidity associated with viral infection emphasizes the need for the development of specific anti-CHIKV drugs. Herein, we describe the development and characterization of a CHIKV reporter replicon cell line and its use in replicon-based screenings. We tested 960 compounds from MMV/DNDi Open Box libraries and identified four candidates with interesting antiviral activities, which were confirmed in viral infection assays employing CHIKV-nanoluc and BHK-21 cells. The most noteworthy compound identified was itraconazole (ITZ), an orally available, safe, and cheap antifungal, that showed high selectivity indexes of >312 and >294 in both replicon-based and viral infection assays, respectively. The antiviral activity of this molecule has been described against positive-sense single stranded RNA viruses (+ssRNA) and was related to cholesterol metabolism that could affect the formation of the replication organelles. Although its precise mechanism of action against CHIKV still needs to be elucidated, our results demonstrate that ITZ is a potent inhibitor of the viral replication that could be repurposed as a broad-spectrum antiviral.

| S-EPMC9317443 | biostudies-literature

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Project description:Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.

| S-EPMC5061146 | biostudies-literature

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| S-EPMC3352666 | biostudies-literature

Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic haematopoietic stem-cell transplantation.

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Project description:Topical conveyance of antifungal agents like itraconazole ITZ has been giving good grounds for expecting felicitous antifungal medicines. The defiance of topical delivery of this poorly water soluble and high-molecular-weight drug, however, mightily entail an adequate vehiculation. ITZ aspasomes, newer antioxidant generation of liposomes, have been designed and enclosed in a cream to ameliorate skin deposition. The proposed creams containing non-formulated ITZ or encapsulated in aspasomes (0.1% or 0.5%) were topically applied in patients with diagnosed diaper dermatitis complicated by candidiasis, tinea corporis (TC), and tinea versicolor (TVC). Placebos (void aspasomal cream and cream base) were also utilized. The obtained results for diaper rash revealed that aspasomal cream (0.5% ITZ) was eminent with respect to complete cure and negative candida culture after 10-day therapy relative to counterparts containing 0.1% ITZ aspasomes or non-formulated ITZ (0.1% and 0.5%). For tinea, the same trend was manifested in terms of 'cleared' clinical response in 90% of patients and absence of fungal elements after 4-week treatment. Relative to non-formulated ITZ, ITZ aspasomal cream was endorsed to be auspicious especially when ITZ concentration was lowered to half commercially available cream concentration (1%), pushing further exploitation in other dermal fungal infections.

| S-EPMC9090397 | biostudies-literature

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