Discovery of Lead 2‑Thiazolylhydrazones with Broad-Spectrum and Potent Antifungal Activity

Opportunistic fungal infections represent a global health
problem,
mainly for immunocompromised individuals. New therapeutical options
are needed since several fungal strains show resistance to clinically
available antifungal agents. 2-Thiazolylhydrazones are well-known
as potent compounds against Candida and Cryptococcus species. A scaffold-focused drug design using machine-learning models
was established to optimize the 2-thiazolylhydrazone skeleton and
obtain novel compounds with higher potency, better solubility in water,
and enhanced absorption. Twenty-nine novel compounds were obtained
and most showed low micromolar MIC values against different species
of Candida and Cryptococcus spp.,
including Candida auris, an emerging
multidrug-resistant yeast. Among the synthesized compounds, 2-thiazolylhydrazone 28 (MIC value ranging from 0.8 to 52.17 μM) was selected
for further studies: cytotoxicity evaluation, permeability study in
Caco-2 cell model, and in vivo efficacy against Cryptococcus neoformans in an invertebrate infection
model. All results obtained indicate the great potential of 28 as a novel antifungal agent.