Novel antifungal agents: Triazolopyridines as inhibitors of β-1,6-glucan synthesis

doi:10.1016/j.bmc.2010.06.096

Bioorganic & Medicinal Chemistry

Volume 18, Issue 16, 15 August 2010, Pages 5845-5854

https://doi.org/10.1016/j.bmc.2010.06.096 Get rights and content

Abstract

Preparations and in vitro antifungal activities of triazolopyridines, imidazopyridines, and a pyrazolopyridine were reported. Among those scaffolds, triazolopyridine was found to be the specific inhibitor of the synthesis of β-1,6-glucan, an essential component of the fungal cell wall, and to show potent antifungal activities against several Candida species.

Graphical abstract

Triazolopyridine was discovered as a promising scaffold for novel antifungal agents, inhibiting β-1,6-glucan synthesis.

Introduction

Fungal infection has dramatically increased in immunosuppressed patients such as those with AIDS or who have had organ or marrow transplants over the past decades.1, 2, 3 Currently, some antifungal agents of major drug classes: azoles, polyenes, and candins, have been launched and are demonstrating remarkable success for the treatment of fungal systemic infections.2, 3, 4, 5, 6, 7 However, these usages are often limited mainly due to their unsatisfactory antifungal activity, narrow spectrum, and side effects, causing rapid development of drug resistance and a high rate of mortality.7, 8, 9, 10 In consideration of these facts, alternative agents for the treatment and prevention of fungal infections are urgently required, preferably with a novel mode of action.

Pyridobenzimidazole derivatives 1, 2, and 3 have been reported as antifungal agents inhibiting the synthesis of β-1,6-glucan, an essential component of the fungal cell wall (Fig. 1).11, 12 It was also reported that their primary target was one of the β-1,6-glucan syntheses encoded by KRE6 gene, which was conserved in various fungi, and that no homolog was found in mammalian cells.13, 14, 15 These facts suggest that Kre6p could be a novel target for the treatment of fungal infections. According to the previous structure–activity relationships study (SARs) by Takeshita et al., substituents such as cyano, methyl, phenyl, and (3S)-(dimethylamino)pyrrolidine on the pyridine core of 2 were required for potent antifungal activity against Candida species (Candida spp.).¹² However, the role of the benzene core in the tricyclic scaffold has not been elucidated so far. Although compound 2 showed potent antifungal activity, its physicochemical properties such as water solubility and metabolic stability were not satisfactory for drug therapies. It is known that water solubility and metabolic stability of compounds are often improved by reducing their lipophilicity. If certain bicyclic compounds in which the benzene core was removed from tricyclic 2 showed antifungal activity in the same manner as compound 2, we could reduce lipophilicity and improve their physicochemical properties. Herein, we would like to report the design, synthesis, and evaluation of antifungal activity of novel bicyclic derivatives such as triazolopyridines, imidazopyridines, and a pyrazolopyridine.

Section snippets

Design

As shown in Figure 2, three new heteroaromatic bicyclic scaffolds: triazolopyridines, imidazopyridines, and pyrazolopyridines, were designed. Based on the results reported by Takeshita, substituents such as cyano, methyl, phenyl, and (3S)-(dimethylamino)pyrrolidine on the rings were considered to be essential to show antifungal activity against Candida spp. Therefore, we decided to fix these substituents and to focus on finding efficient substituents on R².

Chemistry

Triazolopyridines 9 and 13–21 were synthesized as depicted in Scheme 1. Imidoate 5 was synthesized from cyanide 4.¹⁶ Compounds 6a–6d17, 18 and 5 were treated with cyanoacetohydrazide to give triazoles 7a–7e. Compound 7a was then condensed with ethyl 2-acetylhexanoate in the presence of ammonium acetate to afford 8, which was chlorinated with POCl₃ followed by the introduction of (3S)-3-(dimethylamino)pyrrolidine to give triazolopyridine 9. Triazolopyridines 13–19 and 21 were obtained from

Results and discussion

Synthesized compounds 9, 13–21, 29, 30, and 36 were evaluated for their in vitro antifungal activity against Saccharomyces cerevisiae (S. cerevisiae), Candida albicans (C. albicans), Candida glabrata (C. glabrata), Candida tropicalis (C. tropicalis), and Candida krusei (C. krusei). Pyridobenzimidazoles 2, 3, and Fluconazole (FLCZ) were used as positive control agents.

The MIC-0 (the lowest drug concentration producing an optically clear well) of the triazolopyridine derivatives 9, 13–16, and 21

Conclusion

We prepared triazolopyridines 9 and 13–21, imidazopyridines 29 and 30, and pyrazolopyridine 36 and evaluated their antifungal activities against Candida spp. Among them, triazolopyridine was found to be the most promising scaffold for specific inhibitors of β-1,6-glucan synthesis with potent antifungal growth inhibition and improved physicochemical properties.

Chemistry

Unless otherwise noted, materials were obtained from commercial suppliers and used without further purification. Melting points were taken on a Yanako MP-500D melting point apparatus and are uncorrected. Optical rotations were measured in a 0.5-dm cell at 25 °C at 589 nm with a HORIBA SEPA-300 polarimeter. ¹H NMR spectra were determined on a JEOL JNM-EX400 spectrometer. ¹³C NMR spectra were determined on a JEOL JNM-ECP500 spectrometer. Chemical shifts are reported in parts per million relative to

Acknowledgments

We thank the members of Biological Research Laboratories IV for the biological evaluation. We also thank the members of Drug Metabolism & Pharmacokinetics Research Laboratories for the physicochemical tests.

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Novel antifungal agents: Triazolopyridines as inhibitors of β-1,6-glucan synthesis

Abstract

Graphical abstract

Introduction

Section snippets

Design

Chemistry

Results and discussion

Conclusion

Chemistry

Acknowledgments

Curr. Opin. Microbiol.

Bioorg. Med. Chem. Lett.

Drugs

Int. J. Antimicrob. Agents

Clin. Infect. Dis.

Clin. Infect. Dis.

Clin. Infect. Dis.

J. Med. Microbiol.

J. Clin. Microbiol.

Clin. Infect. Dis.

Clin. Microbiol. Rev.

Antimicrob. Agents Chemother.