7-[(2S)-2-羟甲基-4-氨基-1-吡咯烷基]氟喹诺酮类化合物的合成及体外抗菌活性

Synthesis and Antibacterial Activity of 7-[(2S)-2-Hydroxymethyl-4-aminopyrrolidin-1-yl]fluoroquinolone Derivatives

用反式-L-羟脯氨酸经对甲苯磺酰氯保护、甲酯化、氧化、肟化、四氢铝锂还原、叔丁氧基羰基保护后脱除对甲苯磺酰保护基,与不同的氟喹诺酮中间体缩合,最后经脱除叔丁氧基羰基等反应得到目标物,结构经1HNMR和FAB-MS确证,并进行了体外抗菌活性试验。结果表明,除化合物13对供试的大部分菌株,特别是对链球菌的体外活性相当于或优于对照药加替沙星和环丙沙星外,其余3个目标物总体活性均低于对照品。

The novel target compounds 13 - 16 were synthesized from L-hydroxyproline by protection with TsCl,esterification, oxidiation, oximation, reduction, protection with (Boc)2O and then detosylation with Na-Hg amalgam to give(2S)-2-hydromethyl-4-(N-tert-butyoxylcarbonyl)aminopyrrolidine, which after hydrolysis, condensed with four quinoloneintermediates respectively to obtain 9 - 12. The antibacterial activity of 13 - 16 were tested in vitro against 10 Gram-positiveand 10 Gram-negative organisms. The compound 13(MIC 0.03 - 0.12mg/ml) showed better activity against Streptococcithan gatifloxacin(MIC 0.12 - 0.5mg/ml) and ciprofloxacin (MIC 0.5 - 2mg/ml). Compounds 14(MIC 0.25 - 16mg/ml) and15(MIC 0.25 - 64mg/ml) have moderate activity against all 20 organisms. The compound 16(MIC>64mg/ml) showed nosignificant activity against all 20 organisms.