Lipophilicity of novel antitumour and analgesic active 8-aryl-2,6,7,8-tetrahydroimidazo[2,1- c][1,2,4]triazine-3,4-dione derivatives determined by reversed-phase HPLC and computational methods

• Published in: European journal of medicinal chemistry 2010-06, Vol.45 (6), p.2644-2649
• Main Authors: Sztanke, Krzysztof, Markowski, Wojciech, Świeboda, Ryszard, Polak, Beata
• Format: Article
• Language: English
• Subjects: Analgesics; Analgesics - chemistry; Analgesics - pharmacology; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Calibration; Cell Line, Tumor; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Computational Biology; Correlation between log (1/LD 50) and log PHPLC; Correlation between RP-HPLC-derived lipophilicity and log Pcalc. values; Derivatives of 8-aryl-2,6,7,8-tetrahydroimidazo[2,1- c][1,2,4]triazine-3,4-dione; Drug-likeness; General aspects; Humans; Hydrophobic and Hydrophilic Interactions; Lethal Dose 50; Lipophilicity; Medical sciences; Neuropharmacology; Partition coefficient, standardization; Pharmacology. Drug treatments; RP-HPLC; Triazines - chemistry; Triazines - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.01.068

Eight novel antitumour and analgesic active 8-aryl-2,6,7,8-tetrahydroimidazo[2,1- c][1,2,4]triazine-3,4-diones ( 1– 8) have been obtained as a bioactive set of substances and their lipophilicity has been studied. The log k values of fifteen reference compounds and eight newly synthesised imidazotriazine-3,4-dione derivatives were determined by reversed-phase high performance liquid chromatography (RP-HPLC) using mixtures of methanol and water as mobile phases with different methanol concentrations. The relationships between log k values of a set of reference compounds (fifteen compounds) and investigated ones (eight compounds) and concentration of methanol was used for determination of the log k water values by extrapolation. The partition coefficients (log P) values for reference compounds measured experimentally were taken from the literature. The calibration equation was then obtained for the standards of known lipophilicity (log P HPLC) and log k water. In next step the partition coefficients of new synthesised solutes were calculated from the calibration equation. For the comparison purpose, additionally the partition coefficients (log P calc.) of the examined imidazotriazine-3,4-diones were calculated by means of the Pallas 3.1.1.2. software. It was found that log k water values as a lipophilicity measure of derivatives correlate well with partition coefficients measured experimentally (log P HPLC). Correlation between the log P HPLC and the logarithm of partition coefficient calculated by Pallas software (log P calc.) is not so satisfactory as that for values determined experimentally. Furthermore, it has been found that the lipophilicity variation of investigated imidazotriazine-3,4-diones ( 1– 8) correlates well with their acute toxicity expressed as log (1/LD 50). The drug-likeness of all the bioactive 8-aryl-2,6,7,8-tetrahydroimidazo[2,1- c][1,2,4]triazine-3,4-diones was assessed on the basis of their structural properties by applying Lipniski's rule of five. The solutes have all four parameters important for the favourable pharmacokinetics in the human body that would make them likely orally active drugs in humans. log P HPLC values of novel biologically active 8-aryl-2,6,7,8-tetrahydroimidazo[2,1- c][1,2,4]triazine-3,4-diones can be regarded as their hydrophobic parameters and these ones were found to be in the range of 0.97–2.63. 1: R = H; 2: R = 2-CH 3; 3: R = 4-CH 3; 4: R = 2-OCH 3; 5: R = 4-OCH 3; 6: R = 3-Cl; 7: R = 4-Cl; 8: R = 3,4-Cl 2.