Towards the rational design of novel drugs based on solubility, partitioning/distribution, biomimetic permeability and biological activity exemplified by 1,2,4-thiadiazole derivatives

Volkova, Тatyana V.; Терехова, И. В.; Silyukov, Oleg I.; Прошин, А. Н.; Bauer‐Brandl, Annette; Perlovich, German L.

doi:10.1039/c6md00545d

Cited by 30 publications

(5 citation statements)

References 36 publications

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“…The {2-[5-(3-chloro-4-methyl-phenylamino- [1,2,4] thiadiazol-3-yl]-1-me thylethyl}-(2,2,6,6-tetramethylpiperidine-4-yl)-amine (I) has been synthesized and proposed for the treatment of Alzheimer's disease [9,10]. Solubility of I in phosphate buffer pH 7.4 at 25°C (S = 5.57 9 10 -3 mol kg -1 ) has been determined in our previous work [10]. Poor solubility of I in biologically relevant medium (pH 7.4) can considerably restrict its pharmacological activity.…”

Section: Introductionmentioning

confidence: 99%

Effect of cyclodextrin complexation on solubility of novel anti-Alzheimer 1,2,4-thiadiazole derivative

Brusnikina

Silyukov

Chislov

et al. 2017

J Therm Anal Calorim

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New 1,2,4-thiadiazole derivative displaying neuroprotective potential and high activity in the treatment of Alzheimer's disease has been synthesized. The objective of this study was to improve the aqueous solubility of this drug-like compound by means of complex formation with native and hydroxypropylated b-cyclodextrins. To this end, aqueous solubility of 1,2,4-thiadiazole derivative was investigated in the presence of b-cyclodextrins. It was shown that the phase solubility diagrams are of B s type demonstrating the initial increase in thiadiazole solubility in solutions of cyclodextrins (concentration up to 0.01 mol kg -1 ) followed by a solubility decrease due to the precipitation of the complexes formed. In comparison with b-cyclodextrin, hydroxypropyl-b-cyclodextrin displays more pronounced solubilizing action since it forms more stable complexes with thiadiazole. Solid complexes of 1,2,4-thiadiazole derivative with b-cyclodextrins were prepared by grinding and freeze-drying methods. DSC, TG, hot-stage microscopy, solid-state 13 C MAS CP/TOSS NMR, powder X-ray diffractometry and FTIR spectroscopy were used to prove the existence of complexes in the solid state. Solubility of the obtained formulations was also examined. It was found that complexes of thiadiazole with hydroxypropyl-b-cyclodextrin exhibited higher solubility in phosphate buffer (pH 7.4) compared with pure thiadiazole and its complexes with b-cyclodextrin.

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Section: Introductionmentioning

confidence: 99%

Effect of cyclodextrin complexation on solubility of novel anti-Alzheimer 1,2,4-thiadiazole derivative

Brusnikina

Silyukov

Chislov

et al. 2017

J Therm Anal Calorim

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“…Since in order to reach a biologic receptor any drug should dissolve in the physiological fluids, distribute in the body tissues, and penetrate through the biological membranes, the properties of solubility, partition and permeability (so-called transport properties) are of a paramount importance for pharmaceutical chemists and have become an essential part of investigations. The knowledge of these properties within a family of closely related compounds can help to establish the prognostic models for the structure–property correlations with the aim of synthesizing drug substances with the improved properties [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Modulation of Distribution and Diffusion through the Lipophilic Membrane with Cyclodextrins Exemplified by a Model Pyridinecarboxamide Derivative

2023

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The main aims of the study were to disclose the influence of the structure on the solubility, distribution and permeability of the parent substances, iproniazid (IPN), isoniazid (INZ) and isonicotinamide (iNCT), at 310.2 K and to evaluate how the presence of cyclodextrins (2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and methylated β-cyclodextrin (M-β-CD)) affects the distribution behavior and diffusion properties of a model pyridinecarboxamide derivative, iproniazid (IPN). The following order of decreasing the distribution and permeability coefficients was estimated: IPN > INZ > iNAM. A slight reduction of the distribution coefficients in the 1-octanol/buffer pH 7.4 and n-hexane/buffer pH 7.4 systems (more pronounced in the first system) was revealed. The extremely weak IPN/cyclodextrins complexes were estimated from the distribution experiments: KC(IPN/HP-β-CD) > KC(IPN/M-β-CD). The permeability coefficients of IPN through the lipophilic membrane—the PermeaPad barrier—were also measured with and without cyclodextrins in buffer solution. Permeability of iproniazid was increased in the presence of M-β-CD and reduced by HP-β-CD.

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“…Taking into account the numerous attempts to predict permeability reported in the literature [ 10 , 11 , 12 ] and our own experience [ 9 , 13 , 14 , 15 ], in the present study, we aimed to find a correlation between the permeability of a number of new fluconazole antifungal derivatives ( Figure 1 ), measured using the lipophilic PermeaPad barrier and several physicochemical properties and descriptors. In addition, we derived a reliable correlation equation for permeability prediction in the framework of the solubility–diffusion theory using the calculated diffusion coefficients in water and 1-octanol and the distribution coefficient in the 1-octanol/buffer pH 7.4 system determined experimentally in the literature [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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

Volkova

Perlovich

2023

Molecules

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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.

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Towards the rational design of novel drugs based on solubility, partitioning/distribution, biomimetic permeability and biological activity exemplified by 1,2,4-thiadiazole derivatives

Cited by 30 publications

References 36 publications

Effect of cyclodextrin complexation on solubility of novel anti-Alzheimer 1,2,4-thiadiazole derivative

Effect of cyclodextrin complexation on solubility of novel anti-Alzheimer 1,2,4-thiadiazole derivative

Modulation of Distribution and Diffusion through the Lipophilic Membrane with Cyclodextrins Exemplified by a Model Pyridinecarboxamide Derivative

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

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