M. El‐Gamal, Seong Jong Kim, C. Oh
Aug 3, 2011
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Influential Citations
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Journal
The Journal of Antibiotics
Abstract
Carbapenems are one of the most potent types of antibacterial agents and are among those used as a last resort against infections in the clinical field. Recently, they have been classified into three classes according to their chemical structures. According to this classification, meropenem belongs to 1b-methylcarbapenems containing (3S)pyrrolidine-3-ylthio moiety.1 The 1b-methyl group slows renal hydrolysis by dehydropeptidase-I (DHP-I) and allows usage as a single agent.2,3 Carbapenems with (3S)-pyrrolidine-3-ylthio moiety are reported for their broad-spectrum and potent antibacterial activity.4 In the present investigation, we report the synthesis and in vitro antibacterial evaluation of three new meropenem analogs against 18 bacterial strains. Our target is to discover new carbapenem derivatives with improved antibacterial activity (Figure 1). Our general synthetic route leading to new carbapenem derivatives involved the preparation of appropriately protected thiols containing pyrrolidine ring as a side chain and coupling reaction with the carbapenem diphenylphosphate, followed by deprotection of the resulting protected carbapenems in a usual manner. The carboxylic acid 1 was treated with ethyl chloroformate and diazomethane to give the diazo compound 2.5,6 Interaction of 2 with hydrobromic acid afforded the a-bromoacetyl derivative 3.5 Nucleophilic substitution of the bromo group of 3 with dimethylamino moiety was carried out using dimethylammonium chloride in the presence of triethylamine to give 4. Formation of the methoxyimino compound 5 was successfully performed by refluxing the carbonyl compound 4 with N-methoxymethanamine hydrochloride in pyridine. Reduction of the carbonyl group of 4 using sodium borohydride afforded the corresponding hydroxyl compound 6. Deprotection of the trityl group to mercaptans 7–9 was achieved by treatment of 4–6 with trifluoroacetic acid in the presence of triethylsilane (Scheme 1). Reaction of the diphenylphosphate derivative 102 with the thiols 7–9 in the presence of diisopropylamine yielded the corresponding 2-substituted carbapenems 11a–c. Deprotection of these compounds by treatment with tetrakis(triphenylphosphine)palladium (0) and tributyltin hydride gave the target compounds Ia–c (Scheme 2). The final products were purified by column chromatography and their purities (495%) were determined by HPLC. Their structures were confirmed by 1H-NMR and LC-MS. MIC values were determined by the agar dilution method using test agar. An overnight culture of bacteria in tryptosoy broth was diluted to about 106 cells per ml with the same broth, and inoculated with an inoculation device onto agar containing serial two-fold dilutions of the test compounds. The organisms were incubated at 37 1C for 18–20 h. The MICs of the test compounds were defined as the lowest concentration that visibly inhibited growth. The in vitro antibacterial activities of the new meropenem analogs Ia–c against Gram-negative and Gram-positive bacteria are listed in Table 1. For comparison, the MIC values of imipenem and meropenem are also listed. Compounds Ia, b displayed superior or similar activities against Gram-positive bacteria to meropenem, and against Gram-negative bacteria except Pseudomonas aeruginosa 5455 and imipenem-resistant Acinetobacter baumannii to imipenem. Compound Ib showed higher or similar activity against Gram-positive bacteria to imipenem also. Of special interest, compound Ia showed better or similar activity against third generation cephalosporinsresistant Enterobacter cloacae and Serratia marcescens and imipenemresistant Pseudomonas aeruginosa to both imipenem and meropenem. OH OH N