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Novel Nitric Oxide Donor-Azole Conjugation Strategy for Efficient Treatment of Cryptococcus neoformans Infections

Fangfang Wang1,2, Jianbing Wu3, Mingke Yuan3

  • 1The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, P. R. China.

Journal of Medicinal Chemistry
|October 11, 2023
PubMed

Insights

Novel nitric oxide (NO)-donating azole derivatives show potent antifungal activity against Cryptococcus neoformans and its biofilms. An intranasal approach with compound 3h effectively treats cryptococcal meningitis (CM), offering a promising new strategy.

Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Infectious Diseases

Background:

  • Invasive fungal infections (IFIs), particularly cryptococcal meningitis (CM), pose significant global health challenges.
  • Drug resistance in fungal pathogens is often linked to biofilm formation, necessitating new therapeutic agents.
  • Nitric oxide (NO) is recognized for its antimicrobial properties, including the inhibition of microbial biofilms.

Purpose of the Study:

  • To design and synthesize novel nitric oxide (NO)-donating azole derivatives as potential antifungal agents.
  • To evaluate the in vitro antifungal activity and mechanism of action of these compounds against Cryptococcus neoformans.
  • To assess the in vivo efficacy of a lead compound for treating cryptococcal meningitis (CM).

Main Methods:

  • Synthesis of three series of novel NO-donating azole derivatives.
  • In vitro assessment of antifungal activity against Cryptococcus neoformans and its biofilms.
  • In vivo evaluation of anti-CM effects using an intranasal delivery method.

Main Results:

  • Compounds 3a and 3e exhibited significant antifungal activity against Cryptococcus neoformans and inhibited biofilm formation, mediated by NO release.
  • A stable analog, 3h, demonstrated marked therapeutic effects against CM when administered via intranasal dropping.
  • Intranasal delivery of 3h bypassed first-pass metabolism and showed enhanced brain permeability across the blood-brain barrier.

Conclusions:

  • Novel NO-donating azole derivatives represent a promising class of antifungal candidates.
  • Compound 3h shows significant potential for treating cryptococcal meningitis (CM) via an effective intranasal administration route.
  • Further research is warranted to explore the therapeutic potential of these compounds and delivery methods for IFIs.

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