2. Academic Validation
  3. Design, Synthesis, and Biological Activity Evaluation of Deuterated Diphenyl Azole Alcohol-Based CYP51 Inhibitors

Design, Synthesis, and Biological Activity Evaluation of Deuterated Diphenyl Azole Alcohol-Based CYP51 Inhibitors

  • J Med Chem. 2025 Jun 12;68(11):12229-12257. doi: 10.1021/acs.jmedchem.5c01068.
Yixiang Sun 1,  Zirui Luo 1,  Kejian Li 1,  Hongjian Wang 2,  Zixuan Gao 1,  Jiachen Zhang 1,  Rongrong Liu 1,  Rui Liu 1,  Xudong Wu 1,  Nian Liu 1,  Haoyu Zhang 1,  Xin Su 3,  Wenbo Yin 4,  Dongmei Zhao 1,  Maosheng Cheng 1
Affiliations

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, Shenyang 110016, China.
  • 2 The School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe, Shenyang 110016, China.
  • 3 The School of life Science and Biopharmaceutical, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe, Shenyang 110016, China.
  • 4 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
PMID: 40461049 DOI: 10.1021/acs.jmedchem.5c01068
Abstract

In recent years, the incidence of invasive Fungal infections (IFIs) has risen significantly, leading to increased clinical use of azole antifungals. However, their therapeutic utility remains limited by emerging drug resistance, inadequate oral bioavailability, and adverse effects. This study focused on optimizing in vivo pharmacokinetic properties through a molecular hybridization strategy, integrating structural features of Oteseconazole and A33. After multiple rounds of structural refinement, a series of deuterated biphenyl aryl azolol derivatives were developed. Compound C52 demonstrated potent broad-spectrum Antifungal activity in vitro, antibiofilm properties, and inhibition of Fungal morphological transition. Notably, it exhibited favorable pharmacokinetic characteristics, with an oral bioavailability (F) of 63.4%. In vivo efficacy studies revealed that the compound significantly prolonged survival in murine models and maintained potent activity against drug-resistant strain 17#. These findings position compound C52 as a promising CYP51-targeting candidate for treating IFIs, establishing a robust chemical foundation for developing next-generation Antifungal therapeutics.

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