Design and synthesis of pyridine-substituted itraconazole analogues with improved antifungal activities, water solubility and bioavailability

Liu, Yu; Liu, Zi‐Ning; Cao, Xufeng; Liu, Xin; He, Haijun; Yang, Yushe

doi:10.1016/j.bmcl.2011.06.062

Cited by 26 publications

(13 citation statements)

References 10 publications

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“…Five representative drimane terpenes, 1 -5, along with their derivatives, 6 -8 ( Figure 1A), were screened for their ability to inhibit C. albicans growth. It was assumed that additional hydroxyl group(s) or oxygen atoms in the molecule enhances water solubility and may improve bioactivity [31]. Molecules 3 -7 possess extra hydroxyl, aldehyde, or acetoxy functions and molecule 8 contains an acetonide moiety in the drimane structure.…”

Section: Resultsmentioning

confidence: 99%

Broad-spectrum antifungal activities and mechanism of drimane sesquiterpenoids

Edouarzin¹,

Horn²,

Paudyal³

et al. 2020

MIC

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Eight drimane sesquiterpenoids including (-)-drimenol and (+)albicanol were synthesized from (+)-sclareolide and evaluated for their antifungal activities. Three compounds, (-)-drimenol, (+)-albicanol, and (1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalene-1carbaldehyde (4) showed strong activity against C. albicans. (-)-Drimenol, the strongest inhibitor of the three, (at concentrations of 8-64 µg/ml, causing 100% death of various fungi), acts not only against C. albicans in a fungicidal manner, but also inhibits other fungi such as Aspergillus, Cryptococcus, Pneumocystis, Blastomyces, Saksenaea and fluconazole resistant strains of C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. auris. These observations suggest that drimenol is a broad-spectrum antifungal agent. At a high concentration (100 μg/ml) drimenol caused rupture of the fungal cell wall/membrane. In a nematode model of C. albicans infection, drimenol rescued the worms from C. albicans-mediated death, indicating drimenol is tolerable and bioactive in metazoans. Genome-wide fitness profiling assays of both S. cerevisiae (nonessential homozygous and essential heterozygous) and C. albicans (Tn-insertion mutants) collections revealed putative genes and pathways affected by drimenol. Using a C. albicans mutant spot assay, the Crk1 kinase associated gene products, Ret2, Cdc37, and orf19.759, orf19.1672, and orf19.4382 were revealed to be involved in drimenol's mechanism of action. The three orfs identified in this study are novel and appear to be linked with Crk1 function. Further, computational modeling results suggest possible modifications of the structure of drimenol, including the A ring, for improving the antifungal activity.

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Section: Resultsmentioning

confidence: 99%

Broad-spectrum antifungal activities and mechanism of drimane sesquiterpenoids

Edouarzin¹,

Horn²,

Paudyal³

et al. 2020

MIC

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“… 97 Similarly, Yang and co-workers prepared antifungal 99 , which showed improved solubility and bioavailability in comparison to other triazole-based agents, by reacting aryl bromide 97 with heterocyclic-containing piperazine 98 ( Scheme 15 b). 98 In addition, urea-containing piperazine 100 also underwent N-arylation as part of the synthesis of antileukemia agent 101 ( Scheme 15 c). 99 In this transformation, Denny and co-workers employed an L6 -based catalyst and a weak base to arrive at the target compound in modest yield (37%).…”

Section: Alkylaminesmentioning

confidence: 99%

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

2016

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Pd-catalyzed cross-coupling reactions that form C–N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds throughout chemical research. A key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present. Selected examples of C–N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compounds, natural products, organic materials, and catalysts.

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“…1), were screened for their ability to inhibit C. albicans growth. It was assumed that additional hydroxyl group(s) or oxygen atoms in the molecule enhances water solubility and may improve bioactivity (16). Molecules 3 – 7 possess extra hydroxyl, aldehyde, or acetoxy function and molecule 8 contains an acetonide moiety in the drimane structure.…”

Section: Resultsmentioning

confidence: 99%

Broad-Spectrum Antifungal Activities and Mechanism of Drimane Sesquiterpenoids

Edouarzin

Horn

Paduyal

et al. 2019

Preprint

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25Eight drimane sesquiterpenoids including (-)-drimenol and (+)-albicanol were synthesized 26 from (+)-sclareolide and evaluated for their antifungal activities. Three compounds, (-)-drimenol, 27 (+)-albicanol, and (1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalene-1-28 carbaldehyde (4) showed strong activity against C. albicans. (-)-Drimenol, the strongest inhibitor 29 of the three, (at concentrations of 8 -64 g/ml, causing 100% death of fungi), acts not only against 30 C. albicans as a fungicidal manner, but also inhibits other fungi such as Aspergillus, Cryptococcus, 31 Pneumocystis, Blastomyces, Fusarium, Rhizopus, Saksenaea and FLU resistant strains of C. 32 albicans, C. glabrata, C. krusei, C. parapsilosis and C. auris. These observations suggest drimenol 33 is a broad-spectrum antifungal agent. At high concentration (100 μg/ml), drimenol caused a 34 rupture of the fungal cell wall/membrane. In a nematode model of C. albicans infection, drimenol 35 rescued the worms from C. albicans-mediated death, indicating drimenol is tolerable and bioactive 36 in a metazoan. Genome-wide fitness profiling assays of both S. cerevisiae (nonessential 37 homozygous and essential heterozygous) and C. albicans (Tn-insertion mutants) collections 38 revealed putative genes and pathways affected by drimenol. Using a C. albicans mutants spot 39 assay, the Crk1 kinase associated gene products, Ret2, Cdc37, and novel putative targets 40 orf19.759, orf19.1672, and orf19.4382 were revealed to be the potential targets of drimenol. 41 Further, computational modeling results suggest possible modification of the structure of drimenol 42 including the A ring for improving antifungal activity. 43 44 45 46 47 48 Life-threatening fungal infections are an important cause of morbidity and mortality, 49 particularly for patients with immune deficiency and those who are undergoing chemotherapeutic 50 treatments. Some of the leading invasive fungal pathogens include Candida sp., Aspergillus sp. 51 and Cryptococcus sp. Currently, the antifungal therapeutic options are limited, especially when 52 compared to available antibacterial agents (1-4). Among the five classes of antifungals, azoles, 53 echiocandins, polyenes, allylamines, and pyrimidine derivatives, only three are used clinically; 54 azoles, echiocandins, and polyenes. Azole drugs, such as fluconazole (FLU), inhibit ergosterol 55 synthesis through inhibition of lanosterol 14--demethylase, impairing formation of the fungal 56 cell wall. Echocandins, such as caspofungin (CAS), block 1,3--glucan synthase and lead to 57 depletion of glucan in fungal cell wall. Polyenes, including amphotericin B (AMB), bind to 58 ergosterol in fungal cell membrane and change the cell membrane transition temperature, resulting 59 in leakage of ions and small organic molecules, and eventual cell death. Allylamines, such as 60 amorolfin, affect ergosterol synthesis by inhibition of squalene epoxidase. Pyrimidines, such as 61 flucytosine (or 5-fluorocytosine), block nucleic acid synthesis,...

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Design and synthesis of pyridine-substituted itraconazole analogues with improved antifungal activities, water solubility and bioavailability

Cited by 26 publications

References 10 publications

Broad-spectrum antifungal activities and mechanism of drimane sesquiterpenoids

Broad-spectrum antifungal activities and mechanism of drimane sesquiterpenoids

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

Broad-Spectrum Antifungal Activities and Mechanism of Drimane Sesquiterpenoids

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