Rational Design and Discovery of CZx-243: A Highly Stable and Orally Bioavailable Triazole CYP51 Inhibitor for the Treatment of Invasive Fungal Infections.

The rapid emergence of drug-resistant invasive fungal infections (IFIs) necessitates novel, highly stable antifungals. Using iodiconazole as a lead, we employed metabolic site blocking and scaffold optimization to design a series of novel CYP51 inhibitors. Compound D27 (CZx-243) emerged as the optimal candidate, exhibiting potent, broad-spectrum in vitro activity against Candida and Cryptococcus species, including fluconazole-resistant strains (MIC = 0.00625-0.25 μg/mL). Mechanistically, CZx-243 inhibited ergosterol biosynthesis, morphological transitions, and biofilms. Pharmacokinetic profiling revealed high microsomal stability (t1/2 > 120 min), excellent oral bioavailability (F = 76.7%), and a manageable drug-drug interaction profile. In vivo, CZx-243 demonstrated an excellent safety profile (no acute toxicity at 500 mg/kg) and profoundly reduced the renal fungal burden in a fluconazole-resistant systemic murine infection model at an oral dose of merely 5 mg/kg. CZx-243 is a highly promising clinical candidate for drug-resistant IFIs.