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

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• 作者：Krzysztof Sztanke ; Wojciech Markowski ; Ryszard &#x15a ; wieboda ; Beata Polak
• 关键词：Lipophilicity ; Derivatives of 8-aryl-2 ; 6 ; 7 ; 8-tetrahydroimidazo[2 ; 1-c][1 ; 2 ; 4]triazine-3 ; 4-dione ; RP-HPLC ; Partition coefficient ; standardization ; Correlation between RP-HPLC-derived lipophilicity and log P_calc. values ; Correlation
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：June 2010
• 年：2010
• 卷：45
• 期：6
• 页码：2644-2649
• 全文大小：204 K

文摘

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/LD₅₀). 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.