Improving the metabolic stability of antifungal compounds based on a scaffold hopping strategy: Design, synthesis, and structure-activity relationship studies of dihydrooxazole derivatives

Zhao, Liyu; Yin, Wenbo; Sun, Yin; Sun, Nannan; Tian, Linfeng; Zheng, Yang; Zhang, Chu; Zhao, Shizhen; X, Su; Cheng, Maosheng

doi:10.1016/j.ejmech.2021.113715

Cited by 15 publications

(21 citation statements)

References 30 publications

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“…Metabolic stability is one of the most important challenges in drug discovery and the basis for the exertion and maintenance of efficacy, which is an important aspect for evaluating druggability. 35 Given the importance of metabolic stability in drug development, we evaluated the stability of inhibitors at an early stage of development.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Based on these in vitro profiles, preliminary pharmacokinetic studies of compound A17 were performed by administering Sprague-Dawley (SD) rats with a 10 mg/kg intravenous (iv) dose of the compound. 35 After iv administration at a dose of 10 mg/kg, compound A17 exhibited a moderate half-life of 1.26 ± 0.31 h and achieved a maximum concentration (C max ) of 3445.0 ± 63.64 ng/mL. The area under the curve (AUC (0−∞) ) was 3028.95 ± 54.15 ng•h/mL (Table 12).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Species-Selective Targeting of Fungal Hsp90: Design, Synthesis, and Evaluation of Novel 4,5-Diarylisoxazole Derivatives for the Combination Treatment of Azole-Resistant Candidiasis

Yin

Liu

et al. 2022

J. Med. Chem.

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Invasive fungal infections are emerging as serious infectious diseases worldwide. Because of the development of antifungal drug resistance, the limited efficacy of the existing drugs has led to high mortality in patients. The use of the essential eukaryotic chaperone Hsp90, which plays a multifaceted role in drug resistance across diverse pathogenic fungal species, is considered to be a new strategy to mitigate the resistance and counter the threat posed by drug-resistant fungi. Thus, a series of 4,5diarylisoxazole analogues as fungal Hsp90 inhibitors were designed and synthesized that had potent synergistic effects with fluconazole in vitro and in vivo. In particular, compound A17 could avoid the potential mammalian toxicity of Hsp90 inhibitors based on key reside differences between humans and fungi. These data support the feasibility of targeting fungal Hsp90 as a promising antifungal strategy and further development of compound A17 as a valuable research probe for the investigation of fungal Hsp90.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Species-Selective Targeting of Fungal Hsp90: Design, Synthesis, and Evaluation of Novel 4,5-Diarylisoxazole Derivatives for the Combination Treatment of Azole-Resistant Candidiasis

Yin

Liu

et al. 2022

J. Med. Chem.

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“…Pharmacokinetic properties are closely related to drug safety and efficacy. − During lead optimization, medicinal chemists seek to design rational structural modification schemes for lead compounds, aiming to obtain favorable pharmacokinetic properties and sufficient bioactivity. Traditional strategies, such as scaffold hopping and bioisosteric replacement, mainly depend on the empirical chemical rules from medicinal chemists. , However, given the rising amount of data and complexity of chemical and biological systems, it is getting more difficult for medicinal chemists to manually extract related chemical rules . Accordingly, researchers developed many computational methods to automatically learn hidden medicinal chemistry knowledge from large data sets for the prediction and optimization of pharmacokinetic properties, such as machine learning-based quantitative structure–activity relationship (QSAR) models − and matched molecular pairs analysis (MMPA). − However, these strategies have certain limitations.…”

Section: Introductionmentioning

confidence: 99%

“…1−3 During lead optimization, medicinal chemists seek to design rational structural modification schemes for lead compounds, aiming to obtain favorable pharmacokinetic properties and sufficient bioactivity. Traditional strategies, such as scaffold hopping 4 and bioisosteric replacement, 5 mainly depend on the empirical chemical rules from medicinal chemists. 4,5 However, given the rising amount of data and complexity of chemical and biological systems, it is getting more difficult for medicinal chemists to manually extract related chemical rules.…”

Section: Introductionmentioning

confidence: 99%

“…Traditional strategies, such as scaffold hopping 4 and bioisosteric replacement, 5 mainly depend on the empirical chemical rules from medicinal chemists. 4,5 However, given the rising amount of data and complexity of chemical and biological systems, it is getting more difficult for medicinal chemists to manually extract related chemical rules. 6 Accordingly, researchers developed many computational methods to automatically learn hidden medicinal chemistry knowledge from large data sets for the prediction and optimization of pharmacokinetic properties, such as machine learning-based quantitative structure−activity relationship (QSAR) models 7−9 and matched molecular pairs analysis (MMPA).…”

Section: Introductionmentioning

confidence: 99%

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IDL-PPBopt: A Strategy for Prediction and Optimization of Human Plasma Protein Binding of Compounds via an Interpretable Deep Learning Method

Lou

Yang

Wang

et al. 2022

J. Chem. Inf. Model.

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The prediction and optimization of pharmacokinetic properties are essential in lead optimization. Traditional strategies mainly depend on the empirical chemical rules from medicinal chemists. However, with the rising amount of data, it is getting more difficult to manually extract useful medicinal chemistry knowledge. To this end, we introduced IDL-PPBopt, a computational strategy for predicting and optimizing the plasma protein binding (PPB) property based on an interpretable deep learning method. At first, a curated PPB data set was used to construct an interpretable deep learning model, which showed excellent predictive performance with a root mean squared error of 0.112 for the entire test set. Then, we designed a detection protocol based on the model and Wilcoxon test to identify the PPB-related substructures (named privileged substructures, PSubs) for each molecule. In total, 22 general privileged substructures (GPSubs) were identified, which shared some common features such as nitrogen-containing groups, diamines with two carbon units, and azetidine. Furthermore, a series of second-level chemical rules for each GPSub were derived through a statistical test and then summarized into substructure pairs. We demonstrated that these substructure pairs were equally applicable outside the training set and accordingly customized the structural modification schemes for each GPSub, which provided alternatives for the optimization of the PPB property. Therefore, IDL-PPBopt provides a promising scheme for the prediction and optimization of the PPB property and would be helpful for lead optimization of other pharmacokinetic properties.

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Design, synthesis, and evaluation of novel 3,4‐isoxazolediamide derivatives for the combination treatment of azole‐resistant candidiasis

Liu

Sun

Gao

et al. 2022

Archiv der Pharmazie

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Invasive fungal infections are emerging as serious infectious diseases worldwide.Due to the frequent emergence of resistance, the cure for invasive fungal infections is often unachievable. The molecular chaperone Hsp90 provides a promising target because it supports survival, virulence, and drug resistance in a variety of pathogens.Herein, we report on the structural optimization and structure-activity relationship studies of 3,4-isoxazolediamide analogs. As a new class of fungal Hsp90 inhibitor, compound B25 was found to have good synergistic effects with fluconazole and to avoid potential mammalian toxicity. It also showed remarkable metabolic stability in vitro. Collectively, B25 could be a promising lead compound for drug discovery targeting fungal Hsp90 and deserves further investigation.

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Improving the metabolic stability of antifungal compounds based on a scaffold hopping strategy: Design, synthesis, and structure-activity relationship studies of dihydrooxazole derivatives

Cited by 15 publications

References 30 publications

Species-Selective Targeting of Fungal Hsp90: Design, Synthesis, and Evaluation of Novel 4,5-Diarylisoxazole Derivatives for the Combination Treatment of Azole-Resistant Candidiasis

Species-Selective Targeting of Fungal Hsp90: Design, Synthesis, and Evaluation of Novel 4,5-Diarylisoxazole Derivatives for the Combination Treatment of Azole-Resistant Candidiasis

IDL-PPBopt: A Strategy for Prediction and Optimization of Human Plasma Protein Binding of Compounds via an Interpretable Deep Learning Method

Design, synthesis, and evaluation of novel 3,4‐isoxazolediamide derivatives for the combination treatment of azole‐resistant candidiasis

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