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

  • J Med Chem. 2026 Jul 23;69(14):17189-17210. doi: 10.1021/acs.jmedchem.6c01073.
Zirui Luo  1 ,  Yixiang Sun  2 ,  Zixuan Gao  1 ,  Nian Liu  1 ,  Haoyu Zhang  1 ,  Xin Su  3 ,  Dongmei Zhao  1 ,  Maosheng Cheng  1
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
  • 2. School of Science, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing 211198, PR China.
  • 3. The School of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
PMID: 42446107 DOI: 10.1021/acs.jmedchem.6c01073
Abstract

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.

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