2. Academic Validation
  3. Novel antifungal triazoles with alkynyl-methoxyl side chains: Design, synthesis, and biological activity evaluation

Novel antifungal triazoles with alkynyl-methoxyl side chains: Design, synthesis, and biological activity evaluation

  • Eur J Med Chem. 2023 Sep 5;257:115506. doi: 10.1016/j.ejmech.2023.115506.
Fei Xie 1,  Yumeng Hao 1,  Liping Li 2,  Ruina Wang 3,  Junhe Bao 1,  Xiaochen Chi 4,  Brian C Monk 5,  Ting Wang 1,  Shichong Yu 1,  Yongsheng Jin 1,  Dazhi Zhang 6,  Tingjunhong Ni 7,  Lan Yan 8
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, School of Pharmacy, Naval Medical University, 325 Guohe Road, Shanghai, 200433, China.
  • 2 Department of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, No.1239 Siping Road, Shanghai, 200072, China.
  • 3 Center of New Drug Research, School of Pharmacy, Naval Medical University, 325 Guohe Road, Shanghai, 200433, China.
  • 4 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
  • 5 Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, 9016, New Zealand.
  • 6 Department of Organic Chemistry, School of Pharmacy, Naval Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: [email protected].
  • 7 Department of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, No.1239 Siping Road, Shanghai, 200072, China. Electronic address: [email protected].
  • 8 Center of New Drug Research, School of Pharmacy, Naval Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: [email protected].
PMID: 37216811 DOI: 10.1016/j.ejmech.2023.115506
Abstract

Previous work led to the rational design, synthesis and testing of novel Antifungal triazole analogues bearing alkynyl-methoxyl side chains. Tests of in vitro Antifungal activity showed Candida albicans SC5314 and Candida glabrata 537 gave MIC values of ≤0.125 μg/mL for most of the compounds. Among these, compounds 16, 18, and 29 displayed broad-spectrum Antifungal activity against seven human pathogenic Fungal species, two fluconazole-resistant C. albicans isolates and two multi-drug resistant Candida auris isolates. Moreover, 0.5 μg/mL of 16, 18, and 29 was more effective than 2 μg/mL of fluconazole at inhibiting Fungal growth of the strains tested. The most active compound (16) completely inhibited the growth of C. albicans SC5314 at 16 μg/mL for 24 h, affected biofilm formation and destroyed the mature biofilm at 64 μg/mL. Several Saccharomyces cerevisiae strains, overexpressing recombinant Cyp51s or drug efflux pumps, indicated 16, 18, and 29 targeted CYP51 without being significantly affected by a common active site mutation, but were susceptible to target overexpression and efflux by both MFS and ABC transporters. GC-MS analysis demonstrated that 16, 18, and 29 interfered with the C. albicans ergosterol biosynthesis pathway by inhibition at CYP51. Molecular docking studies elucidated the binding modes of 18 with CYP51. The compounds showed low cytotoxicity, low hemolytic activity and favorable ADMT properties. Importantly, compound 16 showed potent in vivo Antifungal efficacy in the G. mellonella Infection model. Taken together, this study presents more effective, broad-spectrum, low toxicity triazole analogues that can contribute to the development of novel Antifungal agents and help overcome Antifungal resistance.

Keywords

Antifungal activity; Cyp51; Drug resistant; Structure-activity relationships; Synthesis; Triazoles.

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