Penicillin structures

The role of IR spectroscopy in the early penicillin structure studies has been described (B-49MI51103) and the results of more recent work have been summarized (B-72MI51101). The most noteworthy aspect of a penicillin IR spectrum is the stretching frequency of the /3-lactam carbonyl, which comes at approximately 1780 cm" This is in contrast to a linear tertiary amide which absorbs at approximately 1650 cm and a /3-lactam which is not fused to another ring (e.g. benzyldethiopenicillin), which absorbs at approximately 1740 cm (the exact absorption frequency will, of course, depend upon the specific compound and technique of spectrum determination). The /3-lactam carbonyl absorptions of penicillin sulfoxides and sulfones occur at approximately 1805 and 1810 cm respectively. The high absorption frequency of the penicillin /3-lactam carbonyl is interpreted in terms of the increased double bond character of that bond as a consequence of decreased amide resonance, as discussed in the X-ray crystallographic section. Other aspects of the penicillin IR spectrum, e.g. the side chain amide absorptions at approximately 1680 and 1510 cm and the carboxylate absorption at approximately 1610 cm are as expected. 

Due to the importance of penicillins and cephalosporins, which certainly saved the lives of hundreds of millions of people, especially the mechanism of the penicillin biosynthesis was intensively investigated (24). Although total syntheses of penicillins are known now for more than 50 years, this reaction in which both rings of the penicillin structure are formed in one step is still impossible to reproduce for... 

Figure 1.15. Structure of 6-aminopenicillanic acid (a) generalized penicillin structure (b) and side-groups present in two natural penicillins and two semisynthetic penicillins (c)...

The BP utilises formation of a derivative in order to quantify penicillins in formulations. Some penicillins do not have distinctive chromophores a further problem with these molecules is that when they are in suspensions they are not readily extracted away from excipients since they are quite insoluble in organic solvents which are immiscible with water. Using the formation of a complex with the mercuric ion in the presence of imidazole as a catalyst, a derivative of the penicillin structure is produced, which has an absorption maximum between 325 and 345 nm. In the assay, comparison with pure standard for the particular penicillin is carried out rather than relying on a standard A(l%, 1 cm) value. This assay is used by the BP for... 

Attachment of 7-hydroxy-4-methylcoumarin as the releasable group of this side chain generated a penicillin structure that can function as a fluorescence-based reporter substance/diagnostic for the presence of low levels of (3-lactamase enzyme in solution (Scheme 117), [320]. 

Scheme 117 Fluorescence-based penicillin structure having a 7-hydroxy-4-methylcoumarin as releasable group...

Common Name [3-(o-Chlorophenyl)-5-methyl-4-isoxazolyl]penicillin Structural Formula ... 

In 1942, Crowfoot embarked upon the molecular structure of penicillin. Structural studies were essential to help in the synthesis of penicillin, a task which was of vital importance during the war. Fortunately, she had met biochemist Ernst Chain62 some years earlier in the streets of Oxford, and he had promised... 

Like Yardley, Crowfoot had a very strong sense of social responsibility four of her mother s brothers had been killed in the First World War, and her mother had been a strong supporter of the League of Nations. As a result of her beliefs, Crowfoot became a member of the CSAWG and, during the Second World War, chose to demonstrate her pacifist beliefs by her work on the penicillin structure which she felt had the potential of saving lives.68... 

These resemble the penicillins structurally, in mode of action and in general lack of toxicity. They are primarily excreted by the kidney by tubular secretion and some also by glomerular filtration (e.g. cephalothin) or only by glomerular filtration (e.g. cefazolin). Cefoperazone is excreted by the bile. Cefotaxime undergoes hepatic biotransformation to active metabolites. Hypersensitivity reactions are qualitatively similar to those of the penicillins, but the epileptogenic potential is less. 

PenicBlins Resistant to Pemditnase. Modification of the penicillin structure produced a group of drugs including methicillin, oxacillin, cloxacillin, dicloxacillin, and nafcillin that are not susceptible to staphylococcal penicillinase. Their appropriate use is in the treatment of infections caused by strains of Staphylococcus aureus and Staphylococcus epidermidis that produce penicillinase. These include most strains isolated from hospital settings and the general commimity. 

PenicBlins With Extended Spectra of Activity. Further modification of the basic penicillin structure produced ampi-cillin and amoxicillin with broader spectra of activity than the original penicillins. One important organism included in the spectra of these antibiotics is Haemophilus influenzae. These antibiotics are used to treat otitis media and respiratory infections in children. 

Figure 7.4. Generalised reaction catalysed hy -lactamases with penicillins as substrates (i) basic penicillin structure (ii) basic penicilloic acid structure...

Sobotka P, Safauda J. The epUeptogeuic actiou of penicillins structure-activity relationship. J Mol Med 1976 1 151. 

Grover, M., Gulati, M., Singh, B. and Singh, S. (2000) Correlation of penicillin structure with rate constants for basic hydrolysis. Pharm. Pharmacol. Comm., 6, 355-363. 

In section 6.6.1, we described how enzymatic methods have come to dominate the production of e important intermediates used in the manufacture of semi-syndietic P-lactams. In principle, the hydrolytic penicillin acylases may be used in the reverse direction to add acyl groups to 6-AFA. For example, a two-step enzymatic process has been described for the preparation of ampiciliin (D-(-)-a-aminobenz penicillin structure shown in Figure 6.1. ... 

Much of the interest in acylases originated from work with the penicillins. Structurally modified penicillins can by obtained by acylation of 6-aminopenicillamic acid. For example, the semisynthetic penicillins such as amoxicillin and ampicillin are obtained using enzymatic acylation. Acylases are used both to remove the phenyl-acetyl group from the major natural penicillin, penicillin G, and to introduce the modified acyl substituent. 

The majority of allergic reactions are the result of sensitivity to the beta-lactam ring in the penicillin structure. The penicillin is metabolized to a penicilloyl moiety, which binds to plasma albumin. This combination triggers an immune reaction, resulting in massive histamine release. 

Semisynthetic Penicillins Structure and Physical Properties Nomenclature... 

It is probable that the largest number of medicinally directed semi-synthetic agents ever produced containing a specific pharmacophore, the -lactam ring, are the penicillins, cephalosporins and mono-bactams. To these must also be added the synthetic cephems and cephams and the many variations upon those basic themes. Although current figures are not available, it was estimated in 1980 that over 10000 variations on the basic penicillin structure had been made and assayed for their ability to inhibit microbial growth (Hoover, J.R.E., personal communication). 

Inspite of the glaring evidence that cephalosporin C was resistant to S. aureus P-lactamase, besides its prevailing antibacterial activity was inferior in comparison to penicillin N and other penicillin structural analogues. 

FERNAnDEZ-CANON, J.M., PENALVA, M.A., Overexpression of two penicillin structural genes m Aspergillus nidulans. Mol. Gen. Genet., 1995,246, 110-118. 

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