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Download fileIdentification of Thiazoyl Guanidine Derivatives as Novel Antifungal Agents Inhibiting Ergosterol Biosynthesis for Treatment of Invasive Fungal Infections
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posted on 30.06.2021, 09:03 authored by Issei Kato, Yuuta Ukai, Noriyasu Kondo, Kohei Nozu, Chiaki Kimura, Kumi Hashimoto, Eri Mizusawa, Hideki Maki, Akira Naito, Makoto KawaiInvasive fungal infections (IFIs)
are fatal infections, but treatment
options are limited. The clinical efficacies of existing drugs are
unsatisfactory because of side effects, drug–drug interaction,
unfavorable pharmacokinetic profiles, and emerging drug-resistant
fungi. Therefore, the development of antifungal drugs with a new mechanism
is an urgent issue. Herein, we report novel aryl guanidine antifungal
agents, which inhibit a novel target enzyme in the ergosterol biosynthesis
pathway. Structure–activity relationship development and property
optimization by reducing lipophilicity led to the discovery of 6h, which showed potent antifungal activity against Aspergillus fumigatus in the presence of serum, improved
metabolic stability, and PK properties. In the murine systemic A. fumigatus infection model, 6h exhibited
antifungal efficacy equivalent to voriconazole (1e).
Furthermore, owing to the inhibition of a novel target in the ergosterol
biosynthesis pathway, 6h showed antifungal activity against
azole-resistant A. fumigatus.