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

Xingxing Teng,Lianbao Ye,Zhibin Shen,Jinhua Gu,Peiqi Shi,Yuanyuan Wang

doi:10.3390/molecules23123116

Xingxing Teng, Lianbao Ye + Show 4 more

Open Access

https://doi.org/10.3390/molecules23123116

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Journal: Molecules	Publication Date: Nov 28, 2018
Citations: 17	License type: CC BY 4.0

Affiliation: Guangdong Pharmaceutical University

Abstract

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.

Highlights

Fungi are widely distributed in nature and frequently present as pathogens in the animal and plant kingdoms [1]
Our group isolated a variety of phloroglucinols from the plant and activity experiment showed that the phloroglucinols had strong antifungal activity such as the minimal inhibition concentration (MIC) values activity of aspidin BB against some clinical S. aureus was ranged from 15.63 mg/mL to 62.5 mg/mL [13,14,15,16]
In order to increase antifungal activity of phloroglucinol derivatives, in this study, we introduced antifungal pharmacophore allylamine into the methyl phloroglucinol and remained C1–C4 acyl group in C-6 position using pseudoaspidinol as lead compound to obtain novel phloroglucinol derivatives 4–17 (Figure 1)

Summary

Introduction

Fungi are widely distributed in nature and frequently present as pathogens in the animal and plant kingdoms [1]. Despite progress in antifungal therapy, infectious diseases caused by a variety of clinically significant species of fungi remain a major global health concern, due to the development of antifungal drug resistance [2,3]. In order to increase antifungal activity of phloroglucinol derivatives, in this study, we introduced antifungal pharmacophore allylamine into the methyl phloroglucinol and remained C1–C4 acyl group in C-6 position using pseudoaspidinol as lead compound to obtain novel phloroglucinol derivatives 4–17 (Figure 1). The widespread use of allylamine has led to the development of severe drug resistance, which has significantly reduced their efficacy [18] These compounds were synthesized and evaluated for their antifungal activity against Trichophyton rubrum and Trichophyton mentagrophytes in vitro. Molecular docking simulations were conducted to confirm the mechanism of action between the compound and squalene epoxidase (SE)

Chemistry

Evaluation of Antifungal Activity

Docking Studies

Synthesis of Compounds

Conclusions