Antifungal Agents: Design, Synthesis, Antifungal Activity and Molecular Docking of Phloroglucinol Derivatives

Pseudoaspidinol is a phloroglucinol derivative with Antifungal activity and is a major active component of Dryopteris fragrans. In our previous work, we studied the total synthesis of pseudoaspidinol belonging to a phloroglucinol derivative and investigated its antifungal activity as well as its intermediates. However, the results showed these compounds have low antifungal activity. In this study, in order to increase antifungal activities of phloroglucinol derivatives, we introduced antifungal pharmacophore allylamine into the methylphloroglucinol. Meanwhile, we remained C1–C4 acyl group in C-6 position of methylphloroglucinol using pseudoaspidinol as the lead compound to obtain novel phloroglucinol derivatives, synthesized 17 compounds, and evaluated antifungal activities on Trichophyton rubrum and Trichophyton mentagrophytes in vitro. Molecular docking verified their ability to combine the protein binding site. The results indicated that most of the compounds had strong antifungal activity, in which compound 17 were found to be the most active on Trichophyton rubrum with Minimum Inhibitory Concentration (MIC) of 3.05 μg/mL and of Trichophyton mentagrophytes with MIC of 5.13 μg/mL. Docking results showed that compounds had a nice combination with the protein binding site. These researches could lay the foundation for developing antifungal agents of clinical value.

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Antifungal Activity of Maytenin and Pristimerin

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/340787 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 31

Author(s):

Fernanda P. Gullo ◽

Janaina C. O. Sardi ◽

Vânia A. F. F. M. Santos ◽

Fernanda Sangalli-Leite ◽

Nayla S. Pitangui ◽

...

Keyword(s):

Antifungal Activity ◽

Antifungal Agents ◽

Trichophyton Rubrum ◽

Fungal Infections ◽

Human Keratinocytes ◽

Trichophyton Mentagrophytes ◽

Pharmacological Activities ◽

Etiologic Agents ◽

High Incidence ◽

Maytenus Ilicifolia

Fungal infections in humans have increased alarmingly in recent years, particularly in immunocompromised individuals. Among the infections systemic candidiasis, aspergillosis, cryptococcosis, paracoccidioidomycosis, and histoplasmosis mortality are more prevalent and more severe in humans. The current high incidence of dermatophytosis is in humans, especially as the main etiologic agentsTrichophyton rubrumandTrichophyton mentagrophytes. Molecules pristimerin and maytenin obtained from the plantMaytenus ilicifolia(Celastraceae) are known to show various pharmacological activities. This study aimed to evaluate the spectrum of antifungal activity of maytenin and pristimerin and their cytotoxicity in human keratinocytes (NOK cells of the oral mucosa). It was concluded that the best spectrum of antifungal activity has been shown to maytenin with MIC varying from 0.12 to 125 mg/L, although it is also active with pristimerin MIC ranging between 0.12 and 250 mg/L. Regarding the toxicity, both showed to have high IC50. The SI showed high pristimerin against some species of fungi, but SI maytenin was above 1.0 for all fungi tested, showing a selective action of fungi. However, when comparing the two substances, maytenin also showed better results. The two molecules can be a possible prototype with a broad spectrum of action for the development of new antifungal agents.

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The ribosomal protein binding site in Saccharomyces cerevisiae ribosomal 5 S RNA. A conserved protein binding site in 5 S RNA.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)36006-x ◽

1979 ◽

Vol 254 (16) ◽

pp. 7724-7729 ◽

Cited By ~ 3

Author(s):

R.N. Nazar

Keyword(s):

Saccharomyces Cerevisiae ◽

Protein Binding ◽

Ribosomal Protein ◽

Binding Site ◽

Protein Binding Site

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Streptochlorin analogues as potential antifungal agents: Design, synthesis, antifungal activity and molecular docking study

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2021.116073 ◽

2021 ◽

Vol 35 ◽

pp. 116073

Author(s):

Ya Gao ◽

Dai-Chuan Huang ◽

Chang Liu ◽

Zi-Long Song ◽

Jing-Rui Liu ◽

...

Keyword(s):

Molecular Docking ◽

Antifungal Activity ◽

Antifungal Agents ◽

Docking Study ◽

Molecular Docking Study ◽

Design Synthesis

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Functional homology between the yeast regulatory proteins GAL4 and LAC9: LAC9-mediated transcriptional activation in Kluyveromyces lactis involves protein binding to a regulatory sequence homologous to the GAL4 protein-binding site.

Molecular and Cellular Biology ◽

10.1128/mcb.7.12.4400 ◽

1987 ◽

Vol 7 (12) ◽

pp. 4400-4406 ◽

Cited By ~ 50

Author(s):

K D Breunig ◽

P Kuger

Keyword(s):

Protein Binding ◽

Binding Site ◽

Transcriptional Activation ◽

Kluyveromyces Lactis ◽

Regulatory Protein ◽

Binding Activity ◽

Protein Binding Site ◽

Regulatory Sequence ◽

Functional Homology ◽

Beta Galactosidase

As shown previously, the beta-galactosidase gene of Kluyveromyces lactis is transcriptionally regulated via an upstream activation site (UASL) which contains a sequence homologous to the GAL4 protein-binding site in Saccharomyces cerevisiae (M. Ruzzi, K.D. Breunig, A.G. Ficca, and C.P. Hollenberg, Mol. Cell. Biol. 7:991-997, 1987). Here we demonstrate that the region of homology specifically binds a K. lactis regulatory protein. The binding activity was detectable in protein extracts from wild-type cells enriched for DNA-binding proteins by heparin affinity chromatography. These extracts could be used directly for DNase I and exonuclease III protection experiments. A lac9 deletion strain, which fails to induce the beta-galactosidase gene, did not contain the binding factor. The homology of LAC9 protein with GAL4 (J.M. Salmeron and S. A. Johnston, Nucleic Acids Res. 14:7767-7781, 1986) strongly suggests that LAC9 protein binds directly to UASL and plays a role similar to that of GAL4 in regulating transcription.

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An Internal Polypyrimidine-Tract-Binding Protein-Binding Site in the Hepatitis C Virus RNA Attenuates Translation, Which Is Relieved by the 3′-Untranslated Sequence

Virology ◽

10.1006/viro.1998.9541 ◽

1999 ◽

Vol 254 (2) ◽

pp. 288-296 ◽

Cited By ~ 82

Author(s):

Takayoshi Ito ◽

Michael M.C. Lai

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Protein Binding ◽

Binding Site ◽

Protein Binding Site ◽

Polypyrimidine Tract ◽

Hepatitis C Virus Rna ◽

Untranslated Sequence ◽

Polypyrimidine Tract Binding Protein ◽

Virus Rna

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Valine-279 Deletion–Mutation on Arginine Vasopressin Receptor 2 Causes Obstruction in G-Protein Binding Site: A Clinical Nephrogenic Diabetes Insipidus Case and Its Sub-Molecular Pathogenic Analysis

Biomedicines ◽

10.3390/biomedicines9030301 ◽

2021 ◽

Vol 9 (3) ◽

pp. 301

Author(s):

Ming-Chun Chen ◽

Yu-Chao Hsiao ◽

Chun-Chun Chang ◽

Sheng-Feng Pan ◽

Chih-Wen Peng ◽

...

Keyword(s):

Structural Analysis ◽

Protein Binding ◽

Diabetes Insipidus ◽

Binding Site ◽

G Protein ◽

Arginine Vasopressin ◽

Nephrogenic Diabetes Insipidus ◽

Md Simulations ◽

Protein Binding Site ◽

Vasopressin Receptor

Congenital nephrogenic diabetes insipidus (CNDI) is a genetic disorder caused by mutations in arginine vasopressin receptor 2 (AVPR2) or aquaporin 2 genes, rendering collecting duct cells insensitive to the peptide hormone arginine vasopressin stimulation for water reabsorption. This study reports a first identified AVPR2 mutation in Taiwan and demonstrates our effort to understand the pathogenesis caused by applying computational structural analysis tools. The CNDI condition of an 8-month-old male patient was confirmed according to symptoms, family history, and DNA sequence analysis. The patient was identified to have a valine 279 deletion–mutation in the AVPR2 gene. Cellular experiments using mutant protein transfected cells revealed that mutated AVPR2 is expressed successfully in cells and localized on cell surfaces. We further analyzed the pathogenesis of the mutation at sub-molecular levels via long-term molecular dynamics (MD) simulations and structural analysis. The MD simulations showed while the structure of the extracellular ligand-binding domain remains unchanged, the mutation alters the direction of dynamic motion of AVPR2 transmembrane helix 6 toward the center of the G-protein binding site, obstructing the binding of G-protein, thus likely disabling downstream signaling. This study demonstrated that the computational approaches can be powerful tools for obtaining valuable information on the pathogenesis induced by mutations in G-protein-coupled receptors. These methods can also be helpful in providing clues on potential therapeutic strategies for CNDI.

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