Penicillin chemical structures

The first of the antibiotics that found practical use as a therapeutic was penicillin. The success of penicillin initiated a vast screening process all over the world, which resulted in the isolation of a large number of antibiotic substances from various natural sources. Many of these compounds were produced by micro-organisms and prove to be lethal for other micro-organisms. Many of these compounds were also very toxic to humans and could not be used therapeutically. Nevertheless a large number of classes of useful compounds were produced. The chemical structures of members of some of the most important classes are shown in Figure 6.1. 

FIGURE 5.37 Chemical structure of a molecular probe with UV-Vis and fluorescence outputs for penicillin G amidase activity. The phenylacetamide group (red) is a substrate for PGA. The reporter units, 4-nitrophenol and 6-aminoquinoline, provide a visible signal and a fluorescence signal, respectively, upon release. (See the color version of this figure in Color Plates section.)... 

Fig. 1 Chemical structures of some of the most important antibiotics used nowadays divided into the most representative families fluoroquinolones, sulfonamides, penicillins, macrolides, and tetracyclines. Another important antibiotic, chloramphenicol, is also shown...

The large number and diversity of available /3-lactams, mainly penicillins and cephalosporins, necessitate their classification. Penicillins can be classified primarily according to chemical structure. Table 5.2 shows that there is good correspondence between chemical structure and properties. The categorization of cephalosporins into chemically similar groups is not useful because their antimicrobial spectrum is not closely correlated with chemical structure, and classification into generations is based on their spectrum of microbial activity (Table 5.3). 

When grouped on the basis of similarities in their chemical structure, most antibiotics fall into the categories listed in Table 1.17. S-Lactams, which include penicillins and cephalosporins, exhibit a characteristic /i-lactam core ring structure (a four-atom cyclic amide) (Figure 1.14). They induce their bacteriocidal activity by inhibiting the synthesis of peptidoglycan, an essential component of the bacterial cell wall. 

The penicillins are a large group of bactericidal compounds. They can be subdivided and classified by their chemical structure and spectrum of activity. The structure common to all penicillins is a (3-lactam ring fused with a thiazolidine nucleus (Fig. 45.1).The antimicrobial activity of penicillin resides in the (3-lactam ring. Splitting of the (3-lactam ring by either acid hydrolysis or (3-lactamases results in the formation of penicilloic acid, a product without antibiotic activity. Addition of various side chains (R) to the basic penicillin molecule... 

Processes of separation by extraction, distillation, crystallization, or adsorption sometimes are equally possible. Differences in solubility, and hence of separability by extraction, are associated with differences in chemical structure, whereas differences in vapor pressure are the basis of separation by distillation. Extraction often is effective at near-ambient temperatures, a valuable feature in the separation of thermally unstable natural mixtures or pharmaceutical substances such as penicillin. 

After the first successful attempts in 1928 to identify the active biochemicals found in antibacterial molds, followed the rediscovery of penicillin by Fleming, identification of its chemical structure by Hodgkin, and subsequent synthesis by Chain, Heatley, and Florey, which led to the commercial production of penicillin in the mid 1940s [1], Since then, other families of (3-lactam antibiotics have been developed [2, 3], and their massive use worldwide continues to be a forefront line of action against infectious pathogens [4-6]. In recent years, (3-lactams have found other biomedical applications, such as inhibitors of serine protease ([7, 8] for a review, see [9]) and inhibitors of acyl-CoA cholesterol acyltransferasa (ACAT) [10]. Encouraged by their bioactivity, the synthesis and chemistry of (3-lactam antibiotics have been the focus of active research, and chemical modification of some basic structures available from biosynthesis (semisynthetic approaches) as well as the discovery of fully chemical routes to de novo synthesis of (3-lactam... 

In reality, the situation is more subde because very often the synthesis of direct analogues is justified by a desire to improve the existing drug. Thus, for penicillins the chemical structure that surrounds the beta-lactam ring is still being modified. Current antibiotics that have been derived from this research (e.g., the cephalosporins) are more selective, more active on resistant strains, and can be administered by the oral route. They are as different from the parent molecule as a recent car compared to a 40-year-old model In other words, innovation can result from the sum of a great number of stepwise improvements, as well as from a major breakthrough. 

The chemical structures of phenoxymethylpenicillin (penicillin V) and flucloxacillin are shown in Figure A12.1. 

Because penicillins and cephalosporins have a common chemical structure, cross-allergies occur with these drugs. Thus before initiating therapy with a penicillin. 

The cephalosporins are contraindicated in patients with known allergies or intolerances to any of the cephalosporins. Because the penicillins and cephalosporins have a common chemical structure, cross-allergies occur with these drugs. Thus before initiating therapy with a cephalosporin, careful inquiry should be made concerning previous hypersensitivity reactions to the other drugs. Because a secondary vitamin K deficiency can develop with cephalosporin use, the cephalosporins are contraindicated in patients with hemophilia. Cefaclor is also contraindicated in any patient with previous drug-related joint and skin reactions. 

Dorothy Hodgkin, who obtained a Nobel Prize in 1965 for her X-ray diffraction work, wrote, a great advantage of X-ray analysis as a method of chemical structure analysis is its power to show some totally unexpected and surprising structure with, at the same time, complete certainty. Her X-ray diffraction studies are the reason that we now know that penicillin has a /3-lactam structure and that vitamin B, contains what is now known as a corrin ring system. The results of all X-ray diffraction studies are used by chemists and biochemists, and these scientists need to be able to appreciate the significance and extent to which such results are useful and precise. 

From 1935 to 1939 he worked on snake venoms, tumor metabolism, the mechanism of lysozyme action, and the invention and development of methods for biochemical microanalysis. In 1939 he began a systematic study of antibacterial substances produced by microorganisms and the reinvestigation of penicillin. Later he worked on the isolation and elucidation of the chemical structure of penicillin and other natural antibiotics. 

Dorothy Crowfoot Hodgkin (Oxford), Nobel Prize in Chemistry in 1964, determined the chemical structure of penicillin by crystallography, in the early 1940s, enabling synthetic production of derivatives. John Sheehan at MIT... 

---