Elsevier

Bioorganic & Medicinal Chemistry

Volume 7, Issue 9, September 1999, Pages 1933-1940
Bioorganic & Medicinal Chemistry

Synthesis and antifungal activity of coumarins and angular furanocoumarins

https://doi.org/10.1016/S0968-0896(99)00138-8Get rights and content

Abstract

Angelicin, a naturally occurring furanocoumarin, that showed antifungal activity, was considered as a lead structure for a group of synthetic coumarins. Antifungal activities of the synthesized coumarins and angelicin derivatives were reported against Candida albicans, Cryptococcus neoformans, Saccharomyces cerevisiae and Aspergillus niger. Human cell line cytotoxicity of several coumarins was evaluated against KB cells. Angelicin and several potent antifungals showed to be non-toxic in this assay.

Introduction

With the employment of modern chemotherapeutic modalities in the 1960s, susceptible hosts were created for several opportunists and with the advent of the AIDS era in the 1980s, a broad range of opportunistic pathogenic fungi are making their appearance in the medical scene. Ranging from a 75% increase in small hospitals to over 400% increase in some large care centres, Candida is now ranked as the third most common causative agent of nosocomial blood stream infections in most hospitals.1, 2

The development of azoles has revolutionized the treatment of many fungal infections, but still treatment of many of them necessitates application of the highly toxic drug, amphotericin B or a combination of drugs. Emergence of new resistant species of fungi in addition to the poor safety and pharmacokinetics profile, challenges the clinicians in their way to handle the fungal infections.

To produce new generations of antifungal compounds, natural products can be considered a rich source of diverse molecules. There are many antifungal compounds of plant origin. These compounds may be constitutive, which present in the plant tissue most of the times, or induced, that are produced in plants only in special circumstances such as infection. Coumarins can be classified in the latter group.3 According to our previous study, angelicin (Figure 1, Scheme 1) was isolated as the bioactive component of Diplotaenia damavandica, a rare Iranian native plant.4 This coumarin skeleton was considered as the lead structure in the present study. To improve the potency and antifungal profile of the lead structure, different modifications were considered. The antifungal activities of the synthesized coumarins and angelicin derivatives are discussed.

Section snippets

Chemistry

The structures of several known compounds used in this study are shown in Figure 1. Synthetic procedures for the target compounds are summarized in Scheme 1, Scheme 2. Compounds Figure 1, Scheme 1, 6b and 7a,b were synthesized according to Zubı́a et al.5 To synthesize different coumarins and furanocoumarins, umbellifreone (6a) and esculin (9a) were used as the starting material. The 8-substituted series of dihydroxycoumarins were prepared through Claisen rearrangement of compound 9e.

With a few

Results

The antifungal activity of different coumarin derivatives is shown in Table 1. Different angular furanocoumarins Figure 1, Scheme 1 exhibit similar antifungal spectrum and potency. The activity of individual segments (i.e. coumarin 2 and benzofuran 3) are much less compared with the original furanocoumarins. Other compounds with phenolic hydroxyl group (4 and 6a), do not show promising activity either.

Among the alkylamines (5ac), there are some active molecules. In the alkylamine series,

Discussion

Coumarins have a variety of bioactivities including: anticoagulant, estrogenic, dermal photosensitizing, antimicrobial, vasodilator, molluscacidal, anthelmintic, sedative and hypnotic, analgesic and hypothermic activity.9 These compounds may also be considered as a defense tool for plants against fungi.10 Although coumarin inhibits the germination of spores of Aspergillus niger, Penicillium glaucum, and Rhizopus nigricans, novobiocin and other 4-hydroxycoumarins are generally ineffective

Conclusion

Angelicin, a naturally occurring furanocoumarin, which showed antifungal activity, was considered as a lead structure for a group of synthetic coumarins. In many of the synthesized coumarins and angular furanocoumarins, the free 6-OH was found to be important for antifungal activity. The free hydroxyl group at position 7 of the coumarin nucleus, however, is important for antibacterial activity.13

Experimental

Melting points were determined on a Fischer melting point apparatus and are uncorrected. The 1H NMR spectra were recorded on either a JEOL JNM-GX270 or Brucker AM-300 spectrometer, using tetramethylsilane as an internal standard. High-resolution mass spectra were determined on an AEI MS 50 spectrometer equipped with a Mass Spectrometry Services MASPEC data system. IR data were recorded on a NICOLET Magna 750 FT IR instrument equipped with a NICPLAN microscope attachment. Silica gel column

Acknowledgements

The authors wish to thank Dr. T. Harayama for providing samples of 1b, 1c and 1d. We would also like to thank Ms. Bernadette Oreski and Ms. Kathy Koski for performing the cytotoxicity test. This work was supported in part by Ministry of Health, Iran, and Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan.

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