medicinal chemistry- penicillin

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Drugs, Antibiotics, penicillin, synthesis


AntibioticsThe term antibiotic is originated from the word antibiosis [against life]. They are compounds obtained from various species of microorganisms such as bacteria, fungi, actinomycetes. They can suppress the growth of other microorganisms and eventually may destroy them. The difference amongst them may be physical, chemical, pharmacological properties, antibacterial spectra, the mechanism or mode of action. They have made it possible to cure the diseases caused by pneumonia, tuberculosis and meningitis and save the lives of millions of people around the world.

Classification Based on Mechanism of Action(1). Agents that inhibit the synthesis of bacterial cell wall: (eg., penicillins, cephalosporins (similar structures); others are cycloserine, vancomycin, bracitracin and imidazole (antifungal) (2). Agents that act directly on the cell membrane of the microorganisms, affecting permeability, and leading to leakage of intercellular compounds (eg., polymyxin, polyene antifungal agents, nystacin and amphotericin B which bind to cell wall sterols) (3). Agents that affect the function of 30s and 50s ribosomal subunits to cause reversible inhibition of protein synthesis: tetracyclines, erythromycins, chloramphenicol and clindamycin. (4). Agents that bind 30s ribosomal subunit and alter protein synthesis: (5). Agents that affects nucleic acid metabolism:

Classification Based on Chemical structure(1). - lactum antibiotics

(2). Amino glycoside antibiotics(3). Tetracycline antibiotics (4). Polypeptide antibiotics (5). Macrolide antibiotics (6). Lincomycins (7). Other antibiotics

MODIFIED PEPTIDES: PENICILLINS, CEPHALOSPORINS, EXAMPLES OF -LACTAM ANTIBIOTICS Penicillins The penicillins are the oldest of the clinical antibiotics, but are still the most widely used. The first of the many penicillins to be employed on a significant scale was penicillin G (benzylpenicillin), obtained from the fungus Penicillium chrysogenum by fermentation in a medium containing corn-steep liquor. Penicillins contain a fused -lactam-thiazolidine structure, which has its biosynthetic origins in a tripeptide, the components of which are l-aminoadipic acid (formed in -lactam-producing organisms from lysine via piperideine-6-carboxylic acid), l-cysteine and l-valine.

CEPHALOSPORINS -EXAMPLE OF -LACTAM ANTIBIOTICSCephalosporin C is produced commercially by fermentation using cultures of a high-yielding strain of Acremonium chrysogenum (formerly Cephalosporium acremonium). Initial studies of the antibiotic compounds synthesized by Cephalosporium acremonium identified penicillin N (originally called cephalosporin N) as the major component, with small amounts of cephalosporin C. In contrast to the penicillins, cephalosporin C was stable under acidic conditions and also was not attacked by penicillinase (-lactamase). Antibacterial activity was rather low, however, and the antibiotic was poorly absorbed after oral administration. However, the structure offered considerable scope for side-chain modifications, more so than with the penicillins, since it has two side-chains, and this has led to a wide variety of cephalosporin drugs, many of which are currently in clinical use.

Other -Lactams The fused -lactam skeletons found in penicillins and cephalosporins are termed penam and cephem respectively variants containing the basic -lactam ring system are also found in nature. Although these are derived from amino acid precursors, in contrast to the penicillins and cephalosporins, they are not usually the products of NRPS enzymes. Of particular importance is the clavam or oxapenam fused-ring system typified by clavulanic acid from Streptomyces clavuligerus.

Clavulanic acid is usually combined with a standard penicillin, e.g. with amoxicillin (as coamoxyclav) or with ticarcillin, to act as a suicide substrate and provide these agents with protection against class A -lactamases, thus extending their effectiveness against a wider range of organisms.

The naturally occurring monobactams show relatively poor antibacterial activity, but alteration of the side-chain, as with penicillins and cephalosporins, has produced many potent new compounds. Unlike those structures, the non-fused -lactam ring is readily accessible by synthesis, so all analogues are produced synthetically. The first of these to be used clinically is aztreonam.

Gentamicins- Example of Amino glycoside antibiotics- interfere withprotein biosynthesis by acting on the smaller 30S subunit of the bacterial ribosome. Amino glycoside antibiotics are produced in culture by strains of Streptomyces and Micromonospora. Compounds obtained from Streptomyces have been given names ending in -mycin, whilst those from Micromonospora have names ending in -micin. 2-Deoxystreptamine-containing Antibiotics Gentamicin is a mixture of antibiotics obtained from Micromonospora purpurea. Fermentation yields a mixture of gentamicins A, B, and C, from which gentamicin C is separated for medicinal use. This is also a mixture, the main component being gentamicin C1 (5060%), with smaller amounts of gentamicin C1a and gentamicin C2. These three components differ in respect to the side-chain in the purpurosamine sugar. Gentamicin is clinically the most important of the aminoglycoside antibiotics, and is widely used for the treatment of serious infections, often in combination with a penicillin when the infectious organism is unknown.

Tetracycline, a valuable antibiotic is a polyketide which is produced on a large scale from Streptomyces aureofaciens

Erythromycin, a macrolide, is a polyketide produced by Streptomycete is an important antibiotic.

Polymyxins- Examples of polypeptide AntibioticsThe polymyxins are a group of cyclic polypeptide antibiotics produced by species of Bacillus. Polymyxins AE were isolated from Bacillus polymyxa, though polymyxin B and polymyxin E were both subsequently shown to be mixtures of two components. A polypeptide mixture called colistin isolated from Bacillus colistinus was then found to be identical to polymyxin E. PolymyxinB and colistin (polymyxin E) are both used clinically. These antibiotic mixtures respectively contain principally polymyxin B1 with small amounts of polymyxin B2, or predominantly polymyxin E1 ( colistin A) with small amounts of polymyxin E2 ( colistin B) (Figure 7.24).

Vancomycin, a glycopeptide antibiotic produced in cultures of Amycolatopsis orientalis (formerly Streptomyces orientalis) and has activity against Gram-positive bacteria, especially resistant strains of staphylococci, streptococci, and enterococci. Vancomycin is not absorbed orally, so must be administered by intravenous injection. The antibiotic may cause toxicity to ear and kidneys.

The penicillins are complex mixtures of closely related compounds isolated from the beers resulting from fermentation of the molds, Penicillium notatum and Penicillium chrysogenum. The active compounds proved to be amides of 6-aminopenicillanic acid ( 6-APA) (1) with differing acyl groups attached to the amine of the -lactam ring. 6-APA possesses weak but definite antibacterial properties, and its structure represents the minimum structural requirements for the characteristic bioactivity of the penicillins.

The incorporation of an acyl side chain (2), particularly one containing an aryl residue, increases potency by 50 to 200-fold.Thus 6-APA (1) is the penicillin pharmacophore, and the amide function serves to modulate the kind and intensity of antimicrobial activity. All the clinically useful analogs that have reached the marketplace have flowed from this basic fact or have resulted from the adventitious discovery of analogous substances from natural sources.

pent-2-enylpenicillin P-hydroxybenzylpencillin n-heptylpenicillin n-amyllpenicillin

Commercial production of benzylpenicillin (penicillin G)by fermentation of selected high-yielding strains of Penicillium chrysogenum in the presence of phenylacetic acid. Though wild-type Penicillium chrysogenum cultures produced about 70 mg/L , commercial strains can yield more than 50 g/L . Benzylpenicillin was the earliest commercially available member of the penicillin group of antibiotics, and it still remains an important and useful drug for the treatment of many Gram-positive bacteria, including streptococcal, pneumococcal, gonococcal, and meningococcal infections. Benzylpenicillin is destroyed by gastric acid; thus, it is not suitable for oral administration and is best given as intramuscular or intravenous injection of the water-soluble sodium salt. Decomposition under acidic conditions leads to formation of penicillic acid and/or penicillenic acid, depending on pH . The -lactam ring is opened by a mechanism in which the side-chain carbonyl participates, resulting in formation of an oxazolidine ring. At higher pH values, benzylpenicillin suffers simple -lactam ring opening and gives penicilloic acid (Figure 7.38). The strained -lactam (cyclic amide) ring is more susceptible to hydrolysis than the unstrained side-chain amide function, since the normal stabilizing effect of the lone pair from the adjacent nitrogen is not possible due to the geometric restrictions .

At higher pH values, benzylpenicillin suffers simple -lactam ring opening and gives penicilloic acid . The strained -lactam (cyclic amide) ring is more susceptible to hydrolysis than the unstrained side-chain amide function, since the normal stabilizing effect of the lone pair from the adjacent nitrogen is not possible due to the geometric restrictions .

Supplementation of the fermentation medium with acids other than phenylacetic acid was used to provide structurally modified penicillins, though the scope was limited to a series of monosubstituted acetic acids by the specificity of the fungal enzymes involved in activation of the acids to their coenzyme A esters. The mos


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