代表讲稿2DoripenemANewBroa[精品].pptxVIP

Doripenem - A New Broad-Spectrum Carbapenem Antibiotic;SAR of doripenem;From Penicillins To Carbapenems ;Carbapenem before Doripenem;Structure of Doripenem;;Analysis of SAR; Mechanism;b-lactamase stability ;Human renal dehydropeptidase1(DHP1) stability;Antimicrobial Features;Toxic Effects ;Synthesis of doripenem; (1R,5S,6S)-6-[(1R)-1-羟乙基]-2-[(3S,5S)-5-氨磺酰胺基甲基吡咯烷-3-基]巯基-1-甲基-1-碳代-2-青霉烯-3-羧酸 ;; Doripenem was synthesized by the condensation of (2S,4S)-1-t-butoxycarbonyl- 2-(N-t-butoxycarbonyl-sulfamoylamido) methyl-4-mercaptopyrrolidone (7) and (1R,5S,6S)-6- [(1R)-1-hydroxyethyl]-2-diphenoxyphosp hony loxy-1-methyl-1-carba-2-penem-3-carboxylic acid p-nitrobenzylester (8), followed by deprotection with a yield of 50.5%. Compound 7 was obtained from trans-4-hydroxy-L-proline by esterification, protection, reduction, SN2 substitution, Mitsunobu reaction and alcoholysis with a yield of 50.8%. The overall yield was about 26% (based on trans-4-hydroxy-L-proline). 反式-4-羟基-L-脯氨酸经酯化、保护、还原、SN2取代、 Mitsunobu反应、醇解得到（2S,4S)-1-叔丁氧羰基氨磺酰胺基）甲基-4-巯基吡咯烷（7），收率50.8%。7与（1R,5S,6S)-6-[(1R)-1-羟乙基]-2-二苯氧磷酰氧基-1-甲基-1-碳代-2-青霉烯-3-羧酸对硝基苄酯（8）缩合、脱保护，得到多尼培南，收率50.5%（以7计）。总收率接近26%（以反式-4-羟基-L-脯氨酸计）。;;Step 1;Step 2;Step 3;Step 4;Step 5;Step 6;Mitsunobu Reaction; Research is a difficult job for us to challenge. Fighting!;;Comparison of doripenem and other carbapenems on pharmacology;1. Antibacterial activity against G+;Penicillin- susceptible Streptococcus pneumoniae: similar to imipenem ,stronger than meropenem and biapenem Penicillin-resistant Streptococcus pneumoniae: identical with others Enterococcus faecalis: slightly lower than imipenem, strong in contrast to other drugs ;Comparison of the MIC90(μg/ml) for doripenem and three other carbapenems tested against Gram-positive pathogens ;2. Antibacterial activity against G-;Comparison of the MIC90(μg/ml) for doripenem and three other carbapenems tested against Gram-negative pathogens;3. Antibacterial activity ag