Novel antifungal agents: a patent review (2013 - present)

ABSTRACT

Introduction: Superficial infections involving the skin and mucosa are the most common fungal disease in humans. Fungi can also produce invasive infections (IFI), which are increasing in incidence among the growing population of immunocompromised patients, and are characterized by a high mortality rate. Amphotericin B, new triazoles and echinocandins have improved treatment options in IFI. However, the frequency of less common and more resistant fungi, the limited activity of available antifungal drugs and their undesirable side effects reflect the urgent need for the development of new therapeutic strategies.

Areas covered: This review summarizes the patents granted from August 2013 to June 2016 for antifungal compounds, reflecting the advances made by pharmaceutical companies and research groups in the discovery of new natural or synthetic antifungal compounds as well as the improvement of previously patented structures with antifungal activity.

Expert opinion: in the period covered here, progress has been in the development of new antifungal compounds or analogs of existing drugs with broad spectrum of activity, more favorable pharmacokinetic profiles or better bioavailability. However, the development of more promising approaches as antifungal compounds with broader antifungal activity and fungal-specific mechanisms of action are a high priority.

KEYWORDS:

• Polyenes
• antifungal compounds
• fungal cell wall
• azole-based antifungal drugs
• antifungal peptides

Article highlights

• New antifungal drugs with broad spectrum of activity and minimum side effects are an urgent need. Currently used antifungal drugs have enabled progress to the management of fungal infections but serious problems of drug resistance due to their large-scale use and toxicity highlight the need of exploring new alternatives to conventional drugs.

• We review here the patent literature since August 2013 to date, regarding the advances in the development of new antifungal compounds to treat human fungal infections.

• New polyene macrolides targeting the fungal membrane have been registered in the period reviewed here. The invention provides novel broad spectrum molecules which overcome the major limitation of this type of compounds as the new derivatives are water-soluble.

• Regarding compounds inhibiting some steps of the ergosterol biosynthesis, new fluconazole analogs have been registered in the period 2013-to date.

• Cell wall is unique to fungi and constitutes an attractive target for the development of antifungal agents. New echinocandins with increased therapeutic index, as well as new enfumafungin derivatives were patented in this period and are under active development now.

• Two patents on antifungal peptides were registered, and one of them could be useful in applications in material coatings to prevent infections associated with biofilm growth on medical devices

• Novel synthetic compounds with antifungal activity have been patented in this period, including 8-hydroxyquinoline-7-carboxamide, pyrrole, pyrrolo[1,2-a][1,4]-benzodiazepine, 2-(1H-pyrazol-1-yl)phenol, amidine, arylamidine and quinazolinone derivatives.

• Advances have been made in two patents that disclose antifungals with new or non-conventional mechanisms of action, like the novel 8-hydroxyquinoline-7-carboxamide may kill fungal cells by iron chelation and the novel quinazolinone derivatives as inhibitors of the fungal DHODH enzyme.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was funded by Agencia Nacional de Promocion Cientifica y Tecnologica de Argentina (ANPCyT, PICT 2015 3592), and Consejo Nacional de Investigaciones Cientificas y Tecnicas de Agentina (CONICET, PIP 11220155010052400).