Abstract
Two new anticancer-active 1,2,3-triazole-dipyridothiazine hybrids were evaluated for their lipophilicity using thin-layer chromatography (TLC) and computational methods. The experimental lipophilicity was evaluated with mobile phases (mixtures of TRIS buffer and acetone), exploiting a linear correlation between the retention parameter (RM) and the volume of acetone. The relative lipophilicity parameter (RM0) was obtained by extrapolation to 0% acetone concentration. This parameter was intercorrelated with a specific hydrophobic surface area (b) revealing two congeneric subgroups: hybrids of 1,2,3-triazole-2,7-diazaphenothiazines and 1,2,3-triazole-3,6-diazaphenothiazines. The parameter RM0 was converted into the absolute lipophilicity parameter logPTLC using a calibration curve prepared on the basis of compounds of known logP values. Triazole–dipyridothiazine hybrids turned out to be medium lipophilic with logPTLC values of 1.232–2.979. The chromatographically established parameter logPTLC was compared to the calculated lipophilic parameter logPcalcd obtained with various algorithms. The lipophilicity was correlated with molecular descriptors and ADME properties. The new triazole–dipyridothiazine hybrids followed Lipinski’s rule of five. The lipophilicity of these hybrids was dependent on the substituents attached to the triazole ring and the location of the azine nitrogen atoms.
Highlights
Lipophilicity is one of the most crucial physicochemical properties
Lipophilicity contributes to the ADMET characteristics of drugs by contributing to their solubility, permeability through membranes, potency, selectivity, and promiscuity, impacting upon their metabolism and pharmacokinetics, and affecting their pharmacodynamic and toxicological profile [5,6]
The lipophilicity of the tested 1,2,3-triazole-dipyridothiazine hybrids (1–10) was first evaluated using eleven of the most popular computer programs that are available on the online platforms
Summary
Lipophilicity is one of the most crucial physicochemical properties. It plays a fundamental role in determining absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, and, in determining the general appropriateness of drug candidates. There is increasing evidence suggesting that controlling molecular properties, such as lipophilicity, in an optimal range, can improve a drug’s quality and its therapeutic success [1]. Lipophilicity is an important parameter because it constitutes the single most informative and successful physicochemical property in medicinal chemistry [2,3,4]. The quantitative structure–activity relationship (QSAR) demonstrated that lipophilicity, evaluated with varied experimental methods, correlates well with other molecular properties (for example, polarity and the dissociation constant) and topological indices, and performs Lipophilicity contributes to the ADMET characteristics of drugs by contributing to their solubility, permeability through membranes, potency, selectivity, and promiscuity, impacting upon their metabolism and pharmacokinetics, and affecting their pharmacodynamic and toxicological profile [5,6].
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