Antibiotics, lactam chemistry

The development of antibacterial chemotherapy during the past 75 years has spearheaded the successful use of today s drugs to combat bacterial infections. Studies in (3-lactam chemistry were stimulated when (3-lactam ring, the four membered heterocycle, was recognized as a key structural feature as well as a key therapeutic feature of the bicyclic (3-lactam antibiotics such as penicillins, cephalosporins, and other classical antibiotics. The last two decades have registered the discovery of several nonclassical bicyclic (3-lactam antibiotics, e.g., thienamycin and carba-penems of natural origin like olivanic acids, carpetimycin, pluracidomycin, and aspareomycins. 

After the discovery of penicillins and cephalosporins as classical (3-lactam antibiotics and clinically useful active agents, the past few decades have witnessed a remarkable growth in the field of (3-lactam chemistry [1, 2]. The need for potentially effective (3-lactam antibiotics as well as more effective (3-lactamase inhibitors has motivated synthetic organic and medicinal chemists to design new functionalized 2-azetidinones. Besides their clinical use as antibacterial agents, these compounds have also been used as synthons in the preparation of various heterocyclic compounds of biological significance [3-7]. The potential use of some... 

Organometallic reagents in /3-lactam chemistry 88T5615. Stereochemistry of electrophilic substitution in /3-lactams 90KGS1155. /3-Lactam antibiotics (see Section II,D,3,c). 

Reviews of p-lactam chemistry include the use of enolate chemistry in asymmetric synthesis <00RHA33>, the utility of 4-formyI-p-lactams as synthons in stereocontrolled syntheses <01CSR226> and the use of p-lactams in the synthesis of complex nucleoside antibiotics and macrocyclic peptides <00PACl763>. 

Our endeavours in peptide and 6-lactame chemistry concentrate on the use of four component condensations (4CC, Ugi reaction (refs. 1,2,5)) in the synthesis of peptides, B-lactam antibiotics and related compounds. 

Since the advent of penicillin, p-lactam antibiotics have occupied a central role against pathogenic bacteria. Moreover, more and more novel p-lactam antibiotics (Figure 4.3) have been developed due to bacterial tolerance and resistance. Special impetus for research efforts on p-lactam chemistry has been provided by the introduction of the p-lactam synthon method, a term coined by Ojima over 15 years ago, according to which 2-azetidinones can be employed as useful intermediates in organic synthesis. 

Chloroacetoacetic esters are important industrial intermediates used especially for the synthesis of the aniinothia2olylacetic acid side chain of modem cephalosporins (see Antibiotics, P-LACTAMS-cephalosporins). For a review of the chemistry of 4-chloroacetoacetates see Reference 112. 

In conclusion, the penicillin class of compounds continues to be actively studied by the scientific community. While the penicillins are an important part of the physician s armamentarium against infectious disease and will remain so for a considerable time, there is increasing emphasis on the study and use of fermentable penicillins as starting materials for the production of other /3-lactam antibiotics, leading to a wealth of heterocyclic chemistry. 

For summaries of Sheehan s penicillin synthesis and related work, see (a) Fleming, I. Selected Organic Syntheses A Guidebook for Organic Chemists, John Wiley Sons New York, 1973, p. 80 (b) Johnson, F. In The Total Synthesis of Natural Products, Vol. 1, ApSimon, J., Ed., Wiley-Interscience New York, 1973, p. 331 (c) Holden, K.G. In Chemistry and Biology of f-Lactam Antibiotics, Morin, R.B. Gorman, M., Eds., Academic Press New York, 1982, Ch. 2, p. 99. 

Brooks G, Bruton G, Finn MJ, Harbridge JB, Harris MA, Howarth TT, Hunt E, Stirling I, Zomaya I (1985) In Brown AG, Roberts SM (eds) Recent advances in the chemistry of /S-lactam antibiotics. The Royal Society of Chemistry, London, p 280... 

Fig. 6. A Chromatogram of a mixture containing the print molecule (oxacillin), two other p-lactam-antibiotics (penicillin G and penicillin V) and a non- 3-lactam-antibiotic (bacitracin) on an oxacillin imprinted MIP containing 4-vinylpyridine residues, cross-linked with TRIM. The analysis was performed in organic mobile phase (ACN/AcOH,99 l).B Same conditions but using the respective non-imprinted control polymer. C Structures of penicillin V, penicillin G, and oxacillin. Reprinted with permission from Skudar K, Briiggemann O, Wittelsberger A, Ramstrom O (1999) Anal Commun 36 327. Copyright 1999 The Royal Society of Chemistry...

Holden, K. G., Total Synthesis of Penicillins, Cephalosporins and Their Nuclear Analogs in Chemistry and Biology of p-Lactam Antibiotics, Morin, R. B. Gorman, M., Eds. Academic Press New York, 1982 Vol. 2, pp. 99-164. 

A large variety of substituents have been attached to these different skeletons, making the /3-lactam antibiotics one of the most varied chemical classes in medicinal chemistry. In extended structure-activity studies, each position... 

Biegel, A., Gebauer, S., Hartrodt, B., Brandsch, M., Neubert, K and Thondorf, 1. (2005) Three-dimensional quantitative structure-activity relationship analyses of beta-lactam antibiotics and tripeptides as substrates of the mammalian H-E/peptide cotransporter PEPTl.Journal of Medicinal Chemistry, 48, 4410-4419. 

Recent Advances in the Chemistry of Lactam Antibiotics, Royal Society of Chemistry, London. 198L... 

R. B. Morin, M. Gorman (Eds.) (1982). Chemistry arui Biology of fi-Lactam Antibiotics. New York Academic Press. 

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