Conazoles

Heeres, Jan; Meerpoel, Lieven; Lewi, Paul

doi:10.3390/molecules15064129

Cited by 115 publications

(104 citation statements)

References 152 publications

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“…As a result, although azoles represent the leading class of antimycotic agents both in medicine and agriculture (15,21), each new compound has to be discovered and developed empirically by monitoring its action on fungal cell growth. Thus, 1200 fluconazole analogs were synthesized and FIGURE 1.…”

mentioning

confidence: 99%

Structure-Functional Characterization of Cytochrome P450 Sterol 14α-Demethylase (CYP51B) from Aspergillus fumigatus and Molecular Basis for the Development of Antifungal Drugs

Hargrove

Wawrzak

Lamb

et al. 2015

Journal of Biological Chemistry

121

154

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Background:The fungus Aspergillus fumigatus causes human diseases that are treated with CYP51 azole inhibitors. Results: We report crystal structures of A. fumigatus CYP51B complexes with two inhibitors, voriconazole and VNI. Conclusion:The structures reveal fungus-specific features not observed in CYP51 enzymes from other biological kingdoms. Significance: This molecular insight facilitates rational design of novel antifungals without inhibition of human enzymes.

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mentioning

confidence: 99%

Structure-Functional Characterization of Cytochrome P450 Sterol 14α-Demethylase (CYP51B) from Aspergillus fumigatus and Molecular Basis for the Development of Antifungal Drugs

Hargrove

Wawrzak

Lamb

et al. 2015

Journal of Biological Chemistry

121

154

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“…First-generation conazoles, such as miconazole, econazole, and isoconazole, are mainly used to treat superficial mycoses, and second/third-generation conazoles, such as fluconazole and voriconazole, are applied to treat emerging invasive fungal infections (Heeres et al, 2010). Because there is a need for more powerful and easy-to-use antifungal drugs for invasive infections, some conazoles, such as albaconazole, ravuconazole, isavuconazole, and pramiconazole, have been developed and/or marketed.…”

Section: Discussionmentioning

confidence: 99%

Establishment of In Silico Prediction Models for CYP3A4 and CYP2B6 Induction in Human Hepatocytes by Multiple Regression Analysis Using Azole Compounds

Nagai

Konno

Satsukawa

et al. 2016

Drug Metabolism and Disposition

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Drug-drug interactions (DDIs) via cytochrome P450 (P450) induction are one clinical problem leading to increased risk of adverse effects and the need for dosage adjustments and additional therapeutic monitoring. In silico models for predicting P450 induction are useful for avoiding DDI risk. In this study, we have established regression models for CYP3A4 and CYP2B6 induction in human hepatocytes using several physicochemical parameters for a set of azole compounds with different P450 induction as characteristics as model compounds. To obtain a well-correlated regression model, the compounds for CYP3A4 or CYP2B6 induction were independently selected from the tested azole compounds using principal component analysis with fold-induction data. Both of the multiple linear regression models obtained for CYP3A4 and CYP2B6 induction are represented by different sets of physicochemical parameters. The adjusted coefficients of determination for these models were of 0.8 and 0.9, respectively. The fold-induction of the validation compounds, another set of 12 azole-containing compounds, were predicted within twofold limits for both CYP3A4 and CYP2B6. The concordance for the prediction of CYP3A4 induction was 87% with another validation set, 23 marketed drugs. However, the prediction of CYP2B6 induction tended to be overestimated for these marketed drugs. The regression models show that lipophilicity mostly contributes to CYP3A4 induction, whereas not only the lipophilicity but also the molecular polarity is important for CYP2B6 induction. Our regression models, especially that for CYP3A4 induction, might provide useful methods to avoid potent CYP3A4 or CYP2B6 inducers during the lead optimization stage without performing induction assays in human hepatocytes.

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“…Historically, there has been relatively little variation in CYP51 inhibitor metal-binding groups (MBGs). First-generation antifungal drugs, such as miconazole and ketoconazole, utilized the 1-imidazole, a high-affinity ligand for heme iron (53). These drugs also inhibited off-target human hepatic cytochrome P450 enzymes, leading to severe and sometimes fatal liver problems (54).…”

Section: Discussionmentioning

confidence: 99%

Clinical Candidate VT-1161's Antiparasitic Effect In Vitro , Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi

Hoekstra

Hargrove

Wawrzak

et al. 2016

Antimicrob Agents Chemother

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Conazoles

Cited by 115 publications

References 152 publications

Structure-Functional Characterization of Cytochrome P450 Sterol 14α-Demethylase (CYP51B) from Aspergillus fumigatus and Molecular Basis for the Development of Antifungal Drugs

Structure-Functional Characterization of Cytochrome P450 Sterol 14α-Demethylase (CYP51B) from Aspergillus fumigatus and Molecular Basis for the Development of Antifungal Drugs

Establishment of In Silico Prediction Models for CYP3A4 and CYP2B6 Induction in Human Hepatocytes by Multiple Regression Analysis Using Azole Compounds

Clinical Candidate VT-1161's Antiparasitic Effect In Vitro , Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi

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