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Home , Cephem, Penam

Antibiotics History: In 1942, Waksman proposed the widely cited definition that “an is a substance produced by microorganisms, which has the capacity of inhibiting the growth and even of destroying other microorganisms”.

Later proposals have sought to both expand and restrict the definition to include any substance produced by a living organism that is capable of inhibiting the growth or survival of one or more species of microorganisms in low concs.

With the advances made by medicinal chemists to modify naturally occurring antibiotics and to prepare synthetic analogs, it has become necessary to permit the inclusion of semisynthetic and synthetic derivatives in the definition. Classes of Antibiotics 1- b-Lactam antibiotics; two main subclasses are well known: A- Classical b-Lactam antibiotics represented by and . B- Non-Classical b-Lactam antibiotics such as: , oxacephams and carbapenams. 2- Non b-Lactam antibiotics:- a) Aminoglycosides: such as streptomycin and kanamycin. b) Fused ring system: such as tetracyclines c) Macrolides: such as erythromycin and oleandomycin. d) Polypeptides: such as . f) Polyene: such as amphotericin. g) Miscellaneous: such as chloramphenicol

1- b-Lactam antibiotics S S

N N O O 1- 2- (Penicillins) (Cephalosporins)

Classification of Penicillins 1- Natural Penicillins They are commercially produced from the submerged cultures, e.g. H 1 N 6 5 S CH3 2 N O CH3 O 7 4 3 2,2-Dimethyl-6-phenylacetamido-penam-3-carboxylic acid.COO H Properties of benzylpenicillin 1- Active against Gram +ve bacilli (narrow spectrum). 2- Ineffective when taken orally, since it breaks down in the acid of the stomach. 3- Sensitive to all known b-lactamases which are produced by resistant bacteria leading to the catalytic degradation of penicillin. 4- Allergic reactions are suffered by some individuals. 5- Non toxic. A. Nucleophilic attack (by OH-)

H R N S H CH 3 R N S CH3 N O .. CH O 3 HN - CO2 O CH3 O OH OH COOH H COOH Penicilloic acid

H CH3 R N HS S HgCl2 C CH3 + R NH CH2CHO CH3 O HN CH3 O H2N COOH

Penilloic acid COOH Penilloaldehyde penicillamine B. Electrophilic attack (by gastric acidity)

H

R N S R N S CH3 CH3 + N H O CH O N.. CH .. O 3 3 O COOH .. COOH H+

COOH R N S HS CH R N S CH3 3 CH3 HN N O CH3 O HN CH + N 3 CH3 O COOH O COOH R COOH

Penicillenic acid Penicillic acid C. Penicillins sensitive to b-lactamases:- b-Lactamases are enzymes which catalyze the hydrolysis of b-lactam ring.

H H

R N S R N S CH3 CH3 N HN O CH O CH .. O 3 .. O 3 COOH COOH .. + Nu : OH Nu H

b-Lactamase b-Lactamase

H Nu R N S CH3 + b-Lactamase HN O.. CH3 O OH COOH II. Semisynthetic Penicillins Obtained from the natural penicillins through:-

H O S N H2N S CH3 CH3 Penicillin acylase R Cl N N O CH3 CH O O 3 Et3N COOH COOH Benzylpenicillin 6-APA O

R HN S CH3

N CH O 3 COOH Different penicillins Types of semisynthetic penicillins A. Acid stable semisynthetic penicillins Introduction of an electron withdrawing group in the a- position of the amide side chain decreases the nucleophilicity of the side chain amide carbonyl oxygen towards participating in b-lactam ring opening to form penicillenic acid.

N3 H H O N S N S CH3 CH3 N N O CH O CH O 3 O 3 COOH COOH (Penicillin V)

It is more active than penicillin V

This group of drugs is still affected by b-lactamases.

B. b-Lactamase stable penicillins By introducing of a bulky group on the side chain which would sterically block the attack and prevent the fitting of the b-lactamase enzyme on the b-lactam ring.

This could be achieved by:- i- Introduction of an aromatic group having two ortho- positioned methoxy groups to shield the lactam ring, e.g., (2,6-dimethoxyphenylpenicillin) It has no electron withdrawing group on the side chain, so it is acid sensitive and has to be administered by injection.

OCH3 H N S CH3 N OCH O CH 3 O 3 COOH Methicillin ii. By introducing a five-membered heterocyclic isoxazole ring into the side chain with bulky substitution in its near position. This ring acts as a steric shield and also to be electron withdrawing.

R'

Oxacillin R = R' = H R = Cl, R' =H N R = R' = Cl H R = Cl, R' = F O R N S CH3 N CH3 O CH O 3 COOH OCH3 CH CONH S CH3 COOH S N CH O 3 COOH  Introduction of 6-a-methoxy group to penicillins give highly resistant derivatives to bacterial b-lactamases  Not absorbed orally & used as Na salt for parenteral administration.

e.g., . It is also parenteral broad-spectrum penicillin with antipseudomonal activity. It is usually co-administered with

Et N N CONH CH CO

O O C. Broad spectrum penicillins:- The introduction of an amino group in the a-position of the side chain of benzylpenicillin, confers a high degree of acid stability together with enhanced activity against Gram -ve bacteria. The a-amino group is protonated in the gastric juice and acquires electron withdrawing property and the molecule becomes acid resistant. These compounds are sensitive to penicillinase enzyme and could be combined with b-lactamase inhibitors

NH 2 NH2 H HO H N S N S CH CH3 3 N N O CH3 O CH O O 3 COOH COOH

** a-NH2 creates new asymmetric center; D-isomer is 8 times more active > L-isomer. ** The presence of OH gp. increase its oral absorption over ampicillin NH3 NH2 H H N N S Me S Me

O N Me O N Me O O

Zwitterions O Ampicillin esters O O OR

 The existence of NH2 & COOH in the same molecule renders it amphoteric & forms Zwitter ions that its solubility becomes difficult in both acid & alkaline media.  Only 40 % of the dose of Ampicillin is absorbed orally from the GIT To overcome this bad absorption: Esterification of the COOH gp gives prodrugs with ↑ lipid solubility & improves oral bioavailability. The esters are lipophilic compounds e.g. , . They are devoid of antibacterial activity (inactive) in vitro, but hydrolyzed by tissue esterases & liberate ampicillin in vivo. ** Ampicillin is administered orally and parenterally as Na salt. ** Formulations with are also available. Bacampicillin

Pivampicillin Amoxicillin

H H HO CH CO NH S Me

NH2 N Me O COOH

D-(-)-a-Amino-p-hydroxybenzylpenicillin.

 Used as trihydrate for oral administration & as Na salt for parenteral use.

 Used also with

 It has superior oral absorption producing around 2.5 times the plasma peak concentration achieved by comparable doses of ampicillin.

 It’s absorption from G.I.T is unaffected by food. Long acting penicillins Benzathine benzylpenicillin

It is in the penicillin Class of medications. It is slowly absorbed into the circulation, after intramuscular injection ,and hydrolyzed to benzylpenicillin in vivo It is the drug-of-choice when prolonged low concentrations of benzylpenicillin are required and appropriate, allowing prolonged antibiotic action over 2–4 weeks after a single IM dose

19 b-Lactamase Inhibitors the production of b-lactamases increase the threat of bacterial resistance. So how can we combat this dangerous enemy? b-lactamase inhibitors  Suicidal inhibitors with weak antibacterial activity,  but have higher capacity to inactivate many b-lactamases.  Used in combination with penicillins to overcome resistance problems O O  e.g. clavulanic acid & sulbactam. CH S 3 i. Sulbactam CH3 N O COOH A penicillenic acid sulfone available as the sodium salt. It is coadministered with Ampicillin (Unasyn IM or IV) Clavulanic Acid H 4 6 5 O OH 3 N 2 1 O COOH H

Clavulanic acid inhibits the b-lactamase enzyme by irreversible binding to the enzyme and allows the penicillin molecule to attack the in order to destroy the bacterial cell. iii. Tazobactam It is formulated with piperacillin. The combination is mainly used intravenously in intensive care medicine (pneumonia, peritonitis) and

O O CH S 3 N CH2 N N N O COONa

Piperacillin Mechanism of action Through inhibition of bacterial cell wall synthesis. Specifically; inhibition of the biosynthesis of dipeptidoglycan that is needed to provide strength and rigidity to the cell wall. The peptidoglycan layer is a highly cross-linked amino sugar polymer consisting the cell wall of the bacterial cell.

Assay of penicillins Iodometric titration:-

Hydrolysis with NaOH, then add xss of standard I2 solution, xss I2 is titrated with sodium thiosulfate in the presence of starch as indicator.

Cephalosporins Cephalosporins are similar to penicillins in terms of mechanism of action, chemical structure, and toxicities.

Antibiotics 24 Cephalosporins are the second major group of b-lactam antibiotics to be discovered. All cephalosporins molecules are based on C, which was discovered by Edward Abraham and his colleagues in Oxford as a minor component of the antibiotic complex produced by Cephalosporium acremonium. O - S OOC CH (CH2)3 C HN NH N + 3 O CH2OCOCH3 COOH

Antibiotics 25 • The structure of cephalosporin C involves: 1. A six membered dihydrothiazine ring with an acetoxymethyl group at its 3-position. This ring is fused to four membered b-lactam ring. 2. An a-aminoadipoyl side chain, that on hydrolysis yields 7- aminocephalosporanic acid (7ACA).

Antibiotics 26 • Properties of Cephalosporin C 2. Low potency. 3. Not absorbed orally. 4. Non toxic. 5. Relatively stable to acid hydrolysis compared to penicillins. 6. More stable to penicillinase than penicillin G. 7. The 7-aminocephalosporanic acid can be modified at a number of positions to obtain the semisynthetic cephalosporins. 8-Moreover, the likelihood of causing allergic reactions is less. As a result, cephalosporin C became a useful lead compound for the development of better

Antibioticsantibiotics 27 • Nomenclature of the Semisynthetic Cephalosporins

1 S S S 6 H N 7 2 2

N 3 N N 8 5 O CH OCOCH O 4 O CH2OCOCH3 2 3 COOH COOH 3-Cephem Cephalosporanic acid 7- Aminocephalosporanicacid (7-ACA)

Antibiotics 28 7-aminocephalosporinic acid (7-ACA) is used as the precursor of many cephalosporins. Cephalosporin analogues may be formed by reacting 7-ACA with acid chlorides.

Antibiotics 29 Stability of Cephalosporins

H 1 S S R N H N - 2 O H o r O N C N b - l a c t a m a s e C H 2 O R C H O R O O O H 2 C O O H C O O H H 2 O A c y l a s e C e p h a l o s p o r o i c a c i d S H 2 N F r a g m e n t s a n d N C H O R r e a r r a n g e m e n t O 2 p r o d u c t s + C O O H H / H 2 O O 7 - A C A S + R ` C N C H H H 2 O S H C N H N C H 2 H O O 2 N C O O H O C H 2 A n h y d r o d e s a c e t y l C c e p h a l o s p o r o i c a c i d O H 1 S O R N D e s a c e t y l - 7 A C A O N l a c t o n e C H O H O 2 C O O H R = C O C H 3 = A c e t y l H 1 S R N

O N C H O 2 C O O Antibiotics D e s a c e t y l c e p h a l o s p o r i n 30 l a c t o n e Antibiotics 31 First Generation Cephalosporins -Produced between 1960-1970. -Broad-spectrum activity against many Gram- positive bacteria. -They are not significantly active against Gram- negative organisms. -Poor ability to penetrate cerebrospinal fluid.- -Inactive against Pseudomonas.

32 Antibiotics A. Parenteral Agents

Cefalotin (Cephalothin)

7-(2-Thienylacetamido)-3-acetoxymethyl-3-Cephem-4-carboxylic acid

Antibiotics 33 • B. Oral Agents

1 2 i. R = HO CH R = CH3 NH 2

1 2 ii. Cephradine R = CH R = CH3 NH 2

iii. Cephalexine 1 2 R = CH R = CH3

NH2

Antibiotics 34 Cephalexine 7-[(D-a-amino-a-phenyl)acetamido]-3-methyl-3- cephem-4- carboxylic acid.

Antibiotics 35 • Second Generation Cephalosporins Produced between 1970-1980. Broad-spectrum activity especially against Gram-positive bacteria and including H. influenzae and some increased activity against Gram-negative organisms. Some drugs can pass the cerebrospinal fluid. Many drugs are for parenteral use.

Antibiotics 36 • A. Parenteral Agents i. 7-[2-(2-Thienyl)acetamido]-7-a-methoxy-3- carbamoyloxymethyl-3-cephem-4-carboxylic acid. The a-Methoxy group at C-7  steric hindrance  high stability against b-lactamases.

Antibiotics 37 ii. Other parenteral drugs include and . Cefuroxime R = H R = CH(CH3)0Ac

The oxime group increases the stability against β-lactamases

Antibiotics 38 B. Oral Agents i. 7-[(D-a-amino-a-phenyl)acetamido]-3-chloro-3-cephem-3- carboxylic acid.

NH2 H H O S HN N Cl O

HO O

Antibiotics 39

Antibiotics 40 The presence of the iminomethoxy group appears to increase stability against certain β-lactamases

Antibiotics 41 Third Generation Cephalosporins • Produced after1980. • Broader spectrum against Gram-negative organisms on the expense of their Gram-positive activity. They are effective in treating a large variety of infections resistant to many other drugs. • Some drugs have high activity against . • Many drugs are for parenteral use. • More resistance to b-lactamases. • They are very expensive.

42 • A. Parenteral Agents • 7-[(2-Amino-4-thiazolyl)-2-methoxyimino)-acetamido]-3- acetylyloxy-methyl-3-cephem-4-carboxylic acid. It has an excellent broad spectrum activity against Gram -ve and Gram +ve aerobic and anaerobic bacteria.

OCH3 N H H HN S S

N O N O CH3

H2N O O HO O

Antibiotics 43

Antibiotics 44 More pronounced β-lactamase stability, greater anti– pseudomonal activity, and increased activity against some Gram-positive organisms like S. pneumonia and S. yogenes.

Antibiotics 45 • B. Oral Agents 7-[(2-Amino-4-thiazolyl)-2-acetoxyimino)acetamido]-3-ethinyl-3- cephem-4-carboxylic acid.

O H H S HO N O HN O N N O S H2N HO O

Antibiotics 46 During 2008, was one of the highest-selling cephalosporins. Ceftriaxone is marketed by Hoffmann-La Roche under the trade name Rocephin®.

Antibiotics 47 • Fourth Generation Cephalosporins They are recent drugs. Broader spectrum against Gram -ve organisms and low activity against Gram +ve Some drugs have high activity against Haemophilus and Neiseria. Mostly for parenteral use. More resistance to b-lactamases. High penetration into cerebrospinal fluid and very active against meningitis.

Antibiotics 48 •

Antibiotics 49 Fifth Generation Cephalosporins Currently, members of the scientific community have not reached agreement with regards to the use of the term ‘fifth generation cephalosporins’ Nevertheless, compounds that are regarded by some as fifth generation will be briefly mentioned. has been described as a fifth- generation cephalosporin. this compound possesses good anti-Pseudomonal activity. is also another example of a cephalosporin that has been described as fifth- generation.

Antibiotics 50 Fifth Generation Cephalosporins

Antibiotics 51 Structure-Activity Relationship of Cephalosporins

The β-lactam ring is crucial for activity Bicyclic ring system important in increasing ring strain The cis-stereochemistry at the positions highlighted in green is important

Site of modification Site of modification

Antibiotics 52 • 1. Acylation of amino group of 7-ACA  Different Cephalosporins. 2. Acetoxy group at position 3 is easily leaving group in acid medium  inactive lactone ring. 3. 3-Cephem  inactive. 4. Removal of -COOH at C4  inactive. 5. Saturation of the double bond of cephem  inactive. 6. A methoxy group at 7 a-position  increase in resistance against b-lactamases.

Antibiotics 53 7. Replacement of S with O or CH2 of cephem at position 1 No change in activity. 8. Substitution of acetoxy group at position 3 leads to: a. Increase acid stability. b. Broadening of the antibacterial activity. c. Increase penetration  increase in activity against resistant bacteria. d. Decrease in allergenicity.

54 Antibiotics OTHER b-LACTAM ANTIBIOTICS 1. Monobactams

NH O

Antibiotics 55 S O H CH3 H N 2 N N H N N O O SO3H CH HOOC 3 CH3

Antibiotics 56 Aztreonam (Azactam) is a synthetic antibiotic, having a monocyclic, rather than a bicyclic nucleus. • This agent inhibits synthesis of bacterial cell wall by high-affinity binding to penicillin-binding protein (PBP3 ) which is found primarily in aerobic, Gram-negative microbes. • Aztreonam (Azactam) is highly resistant to ß- lactamases.

Antibiotics 57 • Spectrum of activity includes aerobic, Gram- negative bacteria and is similar in activity to aminoglycosides without causing ototoxicity or nephrotoxicity • Aztreonam (Azactam) is effective in treating Gram- negative urinary tract infections, lower respiratory tract, skin, intraabdominal, gynecologic infections and septicemia.

Antibiotics 58 2. • i. • 3-b-[(2-Aminoethyl)thio]-6-(1-hydroxyethyl)-7-oxo-1- azabicyclo[3,2.0]hept-2-ene-2-carboxylic acid • The terminal NH2 in the side chain is a nucleophile which attacks b- lactam ring and decreases stability. • The double bond at C2 increases the reactivity of b-lactam ring opening (More susceptible to hydrolysis in acid and alkaline solutions). Thienamycin is resistant to inactivation by most b- lactamases elaborated by Gram -ve and Gram +ve bacteria and therefore, is effective against many strains that are resistant to penicillins and cephalosporins. OH 6 4 2 CH C 5 3 S 3 NH 1 2 H Antibiotics N 59 O 7 COOH • • It is N-Formimidoylthienamycin, the most successful of a series of chemically stable derivatives of thienamycin in which the primary amino group is converted to a non nucleophilic basic function. Imipenem is hydrolyzed by the renal enzyme dehydropeptidase (DHP-1), so it is protected by being coadministered with Cilastatin which is an inhibitor for DHP-1.

OH H S H3C N NH N H O COOH

Antibiotics 60 O CH3 HOOC HN CH3 H S COONa H2N

Cilastatin Na

Imipenem inhibits bacterial cell wall mucopeptide synthesis and is bactericidal, very wide spectrum among the ß-lactams, providing good coverage of Gram-negative rods, Gram-positive bacteria, and anaerobes.

Antibiotics 61 A semisynthetic carbapenem that has been formulated as the trihydrate for IM infusion. The b-methyl group at C4 confers increased stability to hydrolysis by dehydropeptidase 1 enzyme, thereby eliminating the need for a dehydropeptidase inhibitor in the dosing regimen.

HO CH3 H CH3 CH S 5 4 CON H C 3 3 CH3 N N 2 O 1 COOH

Antibiotics 62