Synthesis and antimicrobial activity of clindamycin analogs: pirlimycin, a potent antibacterial agent
作者:Robert D. Birkenmeyer、Stephen J. Kroll、Charles Lewis、Kurt F. Stern、Gary E. Zurenko
DOI:10.1021/jm00368a020
日期:1984.2
mide. This structural modification results in significantly favorable changes in toxicity, metabolism, and antibacterial potency. Although the in vitro antibacterial activity of clindamycin and pirlimycin are nearly identical, the latter compound is 2-20 times more active than clindamycin when administered to mice experimentally infected with strains of Staphylococcus aureus, Streptococcus pyogenes
描述了一系列克林霉素类似物的制备,其中该分子的天然存在的五元环状氨基酸酰胺部分被四元,六元或七元环状氨基酸酰胺替代。最有趣的化合物是吡霉素(7e,U-57,930E),其中克林霉素的(2S-反式)-4-正丙基丙基部分被(2S-顺式)-4-乙基哌酰胺取代。这种结构修饰导致毒性,新陈代谢和抗菌效力的明显有利变化。尽管克林霉素和吡霉素的体外抗菌活性几乎相同,但当对实验感染金黄色葡萄球菌,化脓性链球菌,肺炎链球菌,脆弱型拟杆菌的小鼠给药时,后者的活性是克林霉素的2-20倍。和伯氏疟原虫。皮下和口服给药后,吡嗪霉素在大鼠和小鼠中被吸收。它很容易穿透小鼠中脆弱的B. gilgilis引起的脓肿,并被隔离在这些脓肿中。皮下注射200 mg / kg剂量后,至少6倍于所需抑制浓度的药物浓度维持6小时。总生物活性的尿排泄仅由完整的吡霉素组成,未检测到其他抗菌活性代谢物。吡美霉素在大鼠和小鼠的给药水平上耐受良好。皮下注射200