Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan.
Drug Dev Ind Pharm. 2013 Sep;39(9):1346-56. doi: 10.3109/03639045.2012.712535. Epub 2012 Sep 20.
Six aminoethyl and aminobutyl esters of ketorolac containing 1-methylpiperazine (MPE and MPB), N-acetylpiperazine (APE and APB) or morpholine (ME and MB), were synthesized and their hydrolysis kinetics were studied. The hydrolysis was studied at pH 1 to 9 (for MPE, APE and ME) and pH 1 to 8 (for MPB, APB and MB) in aqueous phosphate buffer (0.16 M) with ionic strength (0.5 M) at 37°C. Calculation of k(obs), construction of the pH-rate profiles and determination of the rate equations were performed using KaleidaGraph® 4.1. The hydrolysis displays pseudo-first order kinetics and the pH-rate profiles shows that the aminobutyl esters, MPE, APB and MB, are the most stable. The hydrolysis of the ethyl esters MPE, APE and ME, depending on the pH, is either fast and catalyzed by the hydroxide anion or slow and uncatalyzed for the diprotonated, monoprotonated and nonprotonated forms. The hydrolysis of the butyl esters showed a similar profile, albeit it was also catalyzed by hydronium cation. In addition, the hydroxide anion is 105 more effective in catalyzing the hydrolysis than the hydronium cation. The hydrolysis pattern of the aminoethyl esters is affected by the number and pKa of its basic nitrogen atoms. The monobasic APE and ME, show a similar hydrolysis pattern that is different than the dibasic MPE. The length of the side chain and the pKa of the basic nitrogen atoms in the aminoethyl moiety affect the mechanism of hydrolysis as the extent of protonation at a given pH is directly related to the pKa.
合成了酮咯酸的 6 种氨乙基和氨丁基酯，分别含有 1-甲基哌嗪（MPE 和 MPB）、N-乙酰基哌嗪（APE 和 APB）或吗啉（ME 和 MB），并研究了它们的水解动力学。在 pH 值为 1 到 9（对于 MPE、APE 和 ME）和 pH 值为 1 到 8（对于 MPB、APB 和 MB）的条件下，在 37°C 下于 0.16 M 磷酸缓冲液（含 0.5 M 离子强度）中进行水解研究。使用 KaleidaGraph® 4.1 计算 k(obs)、构建 pH-速率曲线并确定速率方程。水解显示出准一级动力学，pH-速率曲线表明氨丁基酯 MPE、APB 和 MB 最为稳定。乙基酯 MPE、APE 和 ME 的水解取决于 pH 值，要么是快速的且受氢氧根阴离子催化，要么是缓慢的且不受二质子化、一质子化和非质子化形式的催化。尽管丁基酯的水解也受到氢离子的催化，但也呈现出类似的模式。此外，氢氧根阴离子比氢离子对水解的催化效率高 105 倍。氨乙基酯的水解模式受其碱性氮原子的数量和 pKa 的影响。单碱基 APE 和 ME 显示出相似的水解模式，与双碱基 MPE 不同。氨乙基部分侧链的长度和碱性氮原子的 pKa 影响水解机制，因为在给定 pH 值下的质子化程度与 pKa 直接相关。
