Permeability of New Antifungal Fluconazole Derivatives through a Lipophilic Membrane: Experiment and Modeling

Relationships between the structures of molecules and their properties form the basis of modern chemistry and lay the foundation for structure-based drug design. Being the main two determinants of bioavailability, solubility and permeability of drugs are widely investigated experimentally and predic...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2023-01, Vol.28 (1), p.389
Main Authors: Volkova, Tatyana V, Perlovich, German L
Format: Article
Language:English
Subjects:
Analysis
Antifungal activity
Antifungal agents
Bioavailability
Biomimetics
Dependence
Diagnosis
Diffusion
Dosage and administration
Drug development
Drug therapy
Fluconazole
fluconazole derivatives
Fungal infections
Fungicides
Ionization
Lipophilic
lipophilic membrane
Lipophilicity
Membrane permeability
Membranes
Methods
Molecular weight
Mycoses
Patient outcomes
Permeability
PermeaPad barrier
Pharmaceuticals
Solubility
Solvents
structure–permeability relationship
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Summary:Relationships between the structures of molecules and their properties form the basis of modern chemistry and lay the foundation for structure-based drug design. Being the main two determinants of bioavailability, solubility and permeability of drugs are widely investigated experimentally and predicted from physicochemical parameters and structural descriptors. In the present study, we measure the passive diffusion permeability of a series of new fluconazole derivatives with triazole and thiazolo-pyrimidine moieties connected by different linker bridges through the PermeaPad barrier-a relatively new biomimetic lipophilic membrane that has been increasingly used in recent years. The permeability coefficients of new derivatives are shown to be dependent both on the structure of the linker fragment and on the substituent in the phenyl ring of the thiazolo-pyrimidine moiety. The impact of the compound ionization state on the permeability is revealed. Reliable correlations of the permeability with the antifungal activity and distribution coefficient are found. In addition, the solubility-diffusion approach is shown to be able to successfully predict the permeability of the studied derivatives. The obtained results can be considered another step in the development of permeability databases and design of schemes for in vitro permeability prediction.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules28010389