МОЛЕКУЛЯРНИЙ ДИЗАЙН ТА ПРОГНОСТИЧНА ОЦІНКА ВЛАСТИВОСТЕЙ СПОЛУК СЕРІЇ 5-(2-ОКСОІНДОЛІН-3-ІЛІДЕН) ЗАМІЩЕНИХ ПОХІДНИХ 3-(БЕНЗО[d]ТІАЗОЛ-2-ІЛАМІНО)-2-ТІОКСОТІАЗОЛІДИН-4-ОНУ
Л. М. Мосула, Н. І. Винницька, В. С. Мосула · Art of Medicine · 2025
At the early stage of Drug Discovery, the analysis of the similarity of new structures to drug molecules is crucial, as the chemical structure of a molecule significantly influences its activity. To preliminarily assess the potential of model compounds as possible therapeutic agents, it is advisable to determine the physicochemical and pharmacokinetic parameters to establish the ADME (A – Absorption, D – Distribution, M – Metabolism, E – Elimination) profile of the compounds. This can be achieved through the application of computational prediction methods. Virtual compound design and predictive evaluation of their physicochemical and pharmacokinetic properties using the in silico method. The study materials included previously synthesized compounds (1–4) and virtually modelled derivatives (compounds 7–21) based on 3-(benzo[d]thiazol-2-ylamino)-2-thioxothiazolidin-4-one. The method of study involved the SwissADME tool, available for free on the online platform http://www.swissadme.ch/. There was examined the influence of various substituted isatinylidene moieties when introduced into the 5-position of the rhodanine cycle on the oral bioavailability of molecules and determined their physicochemical and pharmacokinetic parameters, drug-like properties, suitability for medicinal chemistry for prediction ADME profiles. The obtained data indicate sufficient biological activity (BS = 0.55), but limited oral bioavailability of the compounds. Common to all derivatives of the series are F-Csp3 and TPSA violations. Among the 5-(2-oxoindolin-3-ylidene)-substituted derivatives of 3-(benzo[d]thiazol-2-ylamino)-2-thioxothiazolidin-4-one for compound 6, the smallest number of differences in molecular values from the optimal range of physicochemical criteria of orally available drugs is predicted. According to SwissADME predictions, the molecules do not cross the blood-brain barrier and are characterized by low permeability through the skin (Log Kp from -4,73 to -5,72 cm/s). Despite this, all derivatives of investigated series can be considered druglikeness. They correspond to Lipinski's rule of five. In addition, compounds 1, 2, 4, 5, 11 pass freely through the Ghose filter. Another common positive characteristic of our molecules is the absence of a potential inhibitory effect on CYP2D6. This is important because it is known that this CYP450 isoform is responsible for the metabolism and elimination of approximately 25% of drugs. The calculated index of synthetic accessibility (SA = 3.51–4.18) predicts the relative ease of synthesis of the series compounds. Compound 6 demonstrates the most optimal physicochemical properties, outlining its lipophilicity, water solubility, size, saturation, polarity, and flexibility. The violations of some parameters in the studied series compounds of 5-(2-oxoindolin-3-ylidene)-substituted 3-(benzo[d]thiazol-2-ylamino)- 2-thioxothiazolidin-4-one are not critical according to modern Drug Design criteria. Taking into account the predicted low oral bioavailability of the derivatives of rhodanine with benzothiazole and 2-oxoindoline-3-ylidene moieties, it would be advisable to explore alternative administration routes in the future. To improve certain physicochemical properties and pharmacokinetic parameters of the molecules, structural optimization and carry out targeted synthesis of the most promising compounds.