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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Design, synthesis, and biological evaluation of 2-phenylthiazole CYP51 inhibitors
Kejian Li1, Guoqi Zhang1, Wenzhan Hao1
1Key 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 medchemzhao@163.com.
Abstract:
Fungal pathogens have emerged as one of the most significant threats to global public health. Invasive fungal infections, characterized by high morbidity and mortality rates, have become one of the most severe diseases, posing a substantial threat to human health. In this study, a rational drug design strategy was employed, targeting lanosterol 14α-demethylase (CYP51). Using SCZ-14, a CYP51 inhibitor with moderate antifungal activity, as the lead compound, 27 novel 2-phenylthiazole derivatives were designed and synthesized through two rounds of structural optimization. Among these compounds, compound B9 exhibited potent inhibitory activity against seven common clinically susceptible fungal strains and moderate activity against six fluconazole-resistant fungi strains, and it demonstrated low cytotoxicity. In addition, the preferred compound B9 had good drug-like properties according to the prediction software. In addition, molecular dynamics studies were conducted on compound B9. All the results of the above research show that the target compound B9 is valuable for further study.
Insights
Novel antifungal compound B9 shows potent activity against susceptible and resistant fungal strains with low cytotoxicity. This research highlights B9 as a promising candidate for developing new treatments against invasive fungal infections.
Area of Science:
- Medicinal Chemistry
- Mycology
- Drug Discovery
Background:
- Fungal pathogens pose a significant global health threat, causing invasive infections with high morbidity and mortality.
- Existing antifungal treatments face challenges with resistance and toxicity, necessitating the development of novel therapeutic agents.
Purpose of the Study:
- To design and synthesize novel 2-phenylthiazole derivatives targeting lanosterol 14α-demethylase (CYP51) for antifungal activity.
- To identify a lead compound with potent efficacy against susceptible and resistant fungal strains and favorable drug-like properties.
Main Methods:
- Rational drug design strategy based on a lead CYP51 inhibitor (SCZ-14).
- Synthesis and structural optimization of 27 novel 2-phenylthiazole derivatives.
- Antifungal activity screening, cytotoxicity assessment, drug-likeness prediction, and molecular dynamics studies.
Main Results:
- Compound B9 demonstrated potent inhibition against seven susceptible fungal strains and moderate activity against six fluconazole-resistant strains.
- Compound B9 exhibited low cytotoxicity and favorable drug-like properties based on predictive software.
- Molecular dynamics studies supported the potential of compound B9 as a therapeutic agent.
Conclusions:
- Compound B9 is a promising novel antifungal agent with broad-spectrum activity and good safety profile.
- The developed 2-phenylthiazole derivatives, particularly B9, warrant further investigation for clinical development against invasive fungal infections.
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