91182-51-3Relevant academic research and scientific papers
Identification of Thiazoyl Guanidine Derivatives as Novel Antifungal Agents Inhibiting Ergosterol Biosynthesis for Treatment of Invasive Fungal Infections
Kato, Issei,Ukai, Yuuta,Kondo, Noriyasu,Nozu, Kohei,Kimura, Chiaki,Hashimoto, Kumi,Mizusawa, Eri,Maki, Hideki,Naito, Akira,Kawai, Makoto
, p. 10482 - 10496 (2021/07/26)
Invasive 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 againstAspergillus fumigatusin the presence of serum, improved metabolic stability, and PK properties. In the murine systemicA. fumigatusinfection 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-resistantA. fumigatus.
