Benzylpenicillin penicillin structure

Penicillin was the first antibiotic to find practical use in medicine. Commercial production began in the early 1940s and benzylpenicillin (penicillin G), one of several natural penicillins that differ in the R group boxed in the structure above, became one of the most important of all drugs. Most effective against gram-positive bacteria, at higher con-... 

In 1929, Fleming discovered that the mould Penicillium notatum inhibits the growth of bacteria. In 1941 Florey and Chain succeeded in isolating the active agent, known as penicillin, in the form of its sodium salt. The structural elucidation was achieved by chemical degradation and was confirmed in 1945 by X-ray analysis of penicillin G (benzylpenicillin). The structures were shown to be (3/S,5i ,6/ )-6-(acylamino)-2,2-dimethyl-7-oxopenam-3-carboxylic acids ... 

The basic structure of penicillins is a thiazolidine ring linked to a p-lactam ring to form 6-aminopenicillanic acid, the so called penicillin nucleus (Fig. 1). This acid, obtained from Penicillium chrysogenum cultures, is a precursor for semisynthetic penicillins (ampicdlin, amoxicillin, oxacillin, cloxacillin, dicloxacillin, and methicillin) produced by attaching different side chains to the nucleus. Benzylpenicillin (penicillin G) and phenoxymethylpenicil-lin (penicillin V) are the naturally occurring penicillins. 

The nomenclature of penicillins requires special comment. Compound (2) can be named as follows (a) penicillin G (b) benzylpenicillin (note that the term penicillin may refer to the compound class (1), to the structural fragment (3) or, especially in the medical literature, to compound (2) itself) (c) 6/3-phenylacetamidopenicillanic acid (d) 2,2-dimethyl-6/3-phenylacetamidopenam-3a -carboxylic acid (e) (2S,5i ,6i )-3,3-di-methyl-7-oxo-6-(2-phenylacetamido)-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid and (f) [2S-(2a,5a,6/3)]-3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-4-thia-l-azabicyclo-[3.2.0]heptane-2-carboxylic acid. The numbered system shown in (2) is the one most commonly used in the penicillin literature and will be used in this chapter note that different number is used when (2) is named according to (e) and (f) above. 

The early investigations of the reactions of the penicillin class of compounds were largely of a degradative nature, and were primarily associated with structure elucidation. These have been discussed in detail (B-49MI51102) and some of the principal transformations are outlined in Schemes 2, 3 and 4 using benzylpenicillin as an example. Some of these reactions will be discussed in greater detail later in this section. 

The building blocks for the biosynthesis of benzylpenicillin are three amino acids, a-aminoadipic acid, cysteine and valine, and PAA. The amino acids condense to a tripeptide, ring closure of which gives the penicillin ring structure with an cu-aminoadipyl side-chain, isopenicillin N. The side-chain is then displayed by a phenylacetyl group from PAA to give benzylpenicillin. 

Penicillin and cephalosporin antibiotics are usually classed as P-lactam antibiotics, since their common feature is a lactam function in a four-membered ring, typically fused to another ring system. This second ring takes in the P-lactam nitrogen atom and also contains sulfur. In the case of penicillins, e.g. benzylpenicillin, the second ring is a thiazolidine, and in the cephalosporins, e.g. cephalosporin C, this ring is a dihydrothiazine. What is not readily apparent from these structures is that they are both modified tripeptides and their biosyntheses share a common tripeptide precursor. 

Before interest developed in the structure of penicillin, the imidazo[5,1-b ]thiazole ring system was unknown, and even today, almost all of the examples which have been described are those prepared in connection with penicillin studies. Very mild acidic hydrolysis converts benzylpenicillin methyl ester (293) into benzylpenicillic acid (294) by a mechanism suggested... 

Since the first X-ray structure determination of benzylpenicillin potassium 42 (a penam) in 1949, the structures of a large number of -lactam antibiotics have been reported . Table 2 shows the limiting values of the -lactam ring dimensions in a range of penicillin derivatives . More recent X-ray studies on the penicillin and cephalosporin families of antibiotics have been summarized. 

Benzylpenicillin (1942) is produced by growing one of the penicillium moulds in deep tanks. In 1957 the penicillin nucleus (6-amino-penicillanic acid) was synthesised and it became possible to add various side-chains and so to make semisynthetic penicillins with different properties. It is important to recognise that not all penicillins have the same antibacterial spectrum and that it is necessary to choose between a number of penicillins just as it is between antimicrobials of different structural groups, as is shown below. 

Penicillin (or benzylpenicillin) (32a) (R = CH2Ph) was first dicovered by Sir Alexander Fleming in 1929, who isolated the antibiotic from the fungal strain Penicillium notatum (see Introduction, p. 4). Penicillin is valuable to combat bacterial infections in man and animals. It was first manufactured commercially in 1945 and the first semisynthetic penicillins were introduced in 1954. The penicillins (32) have a common structural feature, namely a p-lactam ring fused to the... 

One of the most common antibiotics is penicillin G (benzylpenicillinic acid), which has the following structure ... 

All penicillins (Fignre 74) are composed of a thiazolidine ring attached to a beta-lactam, which in turn carries a free amide gronp (0=CNH) on which a substitution and an attachment (R) are made. In the case of benzylpenicillin, the R is a benzyl gronp. Penicillin may be metabolized by amidase to 6-aminopenicillanic acid, which has antibacterial activity, or by penicillinase (bacterial beta-lactamase), to penicilloic acid, which is devoid of antibacterial activity bnt is antigenic in natnre and acts as a sensitizing structure. The main sonrce of bacterial resistance to penicillin is in fact the prodnction of penicillinase by the microorganisms. 

The X-ray diffraction analysis of the sodium, potassium and the rubidium salts of the benzylpenicillin showed the presenee of a -lactam ring, thereby fmlher supporting the faet that structure (IV) is the probable structure of penicillin. 

Some idea of the difficulties in determining the structure of the penicillins is illustrated by the conversion of benzylpenicillin in acid solution, first to benzyl-penillic acid and then to benzylpenilloic acid. 

Lactamases are bacterial enzymes, some of which play a crucial role in the resistance of pathogens to /3-lactam antibiotics. They are grouped into four classes (A, B, C, and Classes A, C, and D are serine enzymes using serine as a nucleophile, which are excluded in this text. Class B /3-lactamases include mononuclear zinc(II)-/3-lactamases and dinuclear zinc(II)-/3-lactamases. " A Zn -containing /3-lactamase II hydrolyzes the /3-lactam ring of a variety of penicillins (e.g., benzylpenicillin) and cephalosporins. At pH 7 and 30 ""C, the half-life of benzylpenicillin bound to /3-lactamase II is ca. 0.5 ms. The first structure of the... 

A range of penicillins have been examined as competitive reversible inhibitors of enkephalinase [119,120]. Carfecillin K = 0.18 M) was the most potent inhibitor in the series, whereas cloxacillin (Aj = 27.5 //M), ampicillin (A = 41 //M), nafcillin (A = 59 //M) and carbenicillin (Aj =158 juM) had moderate potency and benzylpenicillin (A = 885 jUM), mezlocillin (Aj = 437 juM) and azlocillin (Kj = 556 //M) were weak inhibitors. Structure-activity relationships within the series have been rationalized... 

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