Hughes R A, Toth I, Ward P, McColm A M, Cox D M, Anderson G J, Gibbons W A
School of Pharmacy, University of London, U.K.
J Pharm Sci. 1992 Aug;81(8):845-8. doi: 10.1002/jps.2600810826.
Lipophilic, double-ester derivatives of beta-lactam antibiotics with methylene, ethylene, and propylene spacers were prepared by crown-ether-assisted coupling of halogenoalkyl esters of 2-(tert-butoxycarbonylamino)decanoic acid to either penicillin G or cefuroxime. The hydroxyethyl ester of penicillin G and the tert-butoxypropyl ester of cefuroxime were also prepared. The lipophilic, double-ester conjugates, the hydroxyethyl ester of penicillin G, and the tert-butoxypropyl ester of cefuroxime showed weak or no antibiotic activity in vitro, as expected. The lipophilic penicillin G conjugates and the tert-butoxypropyl ester of cefuroxime were active in vivo against a nonpenicillinase-producing strain of Staphylococcus aureus after subcutaneous administration. The penicillin G double ester with propylene spacer and the tert-butoxypropyl ester of cefuroxime were inactive in vitro, a fact indicating that both compounds were hydrolyzed in vivo, as desired. After oral administration, the lipophilic, double-ester conjugate of penicillin G with methylene spacer and the tert-butoxypropyl ester of cefuroxime were active.
通过冠醚辅助将2-（叔丁氧羰基氨基）癸酸的卤代烷基酯与青霉素G或头孢呋辛偶联，制备了具有亚甲基、乙烯基和丙烯基间隔基的β-内酰胺抗生素的亲脂性双酯衍生物。还制备了青霉素G的羟乙酯和头孢呋辛的叔丁氧丙酯。如预期的那样，亲脂性双酯缀合物、青霉素G的羟乙酯和头孢呋辛的叔丁氧丙酯在体外显示出微弱或无抗生素活性。亲脂性青霉素G缀合物和头孢呋辛的叔丁氧丙酯在皮下给药后对非产青霉素酶的金黄色葡萄球菌菌株在体内具有活性。具有丙烯基间隔基的青霉素G双酯和头孢呋辛的叔丁氧丙酯在体外无活性，这一事实表明这两种化合物都按预期在体内被水解。口服给药后，具有亚甲基间隔基的青霉素G亲脂性双酯缀合物和头孢呋辛的叔丁氧丙酯具有活性。
