Abstract
The subject of the study was 11 new synthetized tetracyclic diazaphenothiazine derivatives. Using thin-layer chromatography in a reverse phase system (RP-TLC), their RM0 lipophilicity parameter was determined. The mobile phase was composed of 0.2 M Tris buffer (pH = 7.4) and acetone (POCH S.A., Gliwice, Poland) in different concentrations. Using computer programs, based on different computational algorithms, theoretical values of lipophilicity (AClogP, ALOGP, ALOGPs, miLogP, MLOGP, XLOGP2, and XLOGP3) as well as molecular descriptors (molecular weight, volume of a molecule, dipole moment, polar surface, and energy of HOMO orbitals and LUMO orbitals) and parameters of biological activity: human intestinal absorption (HIA), plasma protein binding (PPB), and blood-brain barrier (BBB), were determined. The correlations between the experimental values of lipophilicity and theoretically calculated lipophilic values and also between experimental values of lipophilicity and values of physicochemical or biological properties were assessed. A certain relationship between structure and lipophilicity was found. On the other hand, the relationships between RM0 and physicochemical or biological properties were not statistically significant and therefore unusable. For all analysed values, an analysis of similarities and principal component analyses were also made. The obtained dendrograms for the analysis of lipophilicity and physicochemical and biological properties indicate the relationship between experimental values of lipophilicity and structure in the case of theoretical lipophilicity values only. PCA, on the other hand, showed that ALOGP, MLOGP, miLogP, and BBB and molar volume have the largest share in the description of the entire system. Distribution of compounds on the area of factors also indicates the connections between them related to their structure.
Highlights
Designing new compounds which could find the application as drugs is an expensive and timeconsuming process. ere is ongoing research concerning a new solution that could limit the number of necessary syntheses and at the same time obtain the products with optimal physicochemical properties correlated with biological activity [1]
Derivatives 1–11 were obtained through synthesis of thiochininantrenodiic chloride with a series of substituted aminopyridine derivatives. e methodology was described in our previous work [37]. e basic structure of the unsubstituted pyridoquinothiazine salt containing the nitrogen atom at position 8 of the tetracyclic system was modified by introducing various types of electron-withdrawing substituents and electron donors (Br, Cl, F, I, CH3, and OCH3) in positions 9, 10, and 11 of the pyridine ring
Solutions of pyridoquinothiazine salts 1–11 were prepared by dissolving 1 mg of particular compound in 2 ml of ethanol (POCH S.A., Gliwice, Poland). e solution was spotted into chromatographic plates in the amount of 2 μL by use of microcapillary. e mobile phase was composed of 0.2 M Tris buffer and acetone (POCH S.A., Gliwice, Poland) in different concentrations, i.e., 50%, 60%, 70%, 80%, and 90%. e chromatograms were visualised in UV light (λ 254 nm)
Summary
Using computer programs, based on different computational algorithms, theoretical values of lipophilicity (AClogP, ALOGP, ALOGPs, miLogP, MLOGP, XLOGP2, and XLOGP3) as well as molecular descriptors (molecular weight, volume of a molecule, dipole moment, polar surface, and energy of HOMO orbitals and LUMO orbitals) and parameters of biological activity: human intestinal absorption (HIA), plasma protein binding (PPB), and blood-brain barrier (BBB), were determined. E correlations between the experimental values of lipophilicity and theoretically calculated lipophilic values and between experimental values of lipophilicity and values of physicochemical or biological properties were assessed. The relationships between RM0 and physicochemical or biological properties were not statistically significant and unusable. E obtained dendrograms for the analysis of lipophilicity and physicochemical and biological properties indicate the relationship between experimental values of lipophilicity and structure in the case of theoretical lipophilicity values only. Distribution of compounds on the area of factors indicates the connections between them related to their structure
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