Cephalosporins.pdf

β-Lactam antibiotics B) Cephalosporins Prepared by Dr.Ebtesam Salem 1  Contents Introduction to Cephalosporin Mechanism of action Chemistry of Cephalosporin Nomenclatures Cephalosporins advantages over penicillins Semisynthetic Derivative...

β-Lactam antibiotics B) Cephalosporins Prepared by Dr.Ebtesam Salem 1  Contents Introduction to Cephalosporin Mechanism of action Chemistry of Cephalosporin Nomenclatures Cephalosporins advantages over penicillins Semisynthetic Derivatives Oral & parenteral Cephalosporins SAR of cephalosporins Classification of cephalosporins 2 Prepared by Dr.Ebtesam Salem  Introduction to Cephalosporin They are β-lactam antibiotics with same fundamental structural requirements as penicillins. It originally isolated as a product of fermentation from the fungus Cephalosporium acremonium The three principal antibiotic components are isolated: 1. Cephalosporin N: It has a penicillin-like structure 2. Cephalosporin P: An acidic antibiotic, which is steroidal in nature. 3. Cephalosporin-C: It is a true cephalosporin and it is a derivative of 7 amino-cephalosporanic acid 3 4 Prepared by Dr.Ebtesam Salem  Mechanism of action The cephalosporins have a mechanism of action similar to that of penicillins, They are bactericidal. The cephalosporins act by inhibition bacterial cell walls synthesis by inhibiting transpeptidase enzyme. They disrupt synthesis of the peptidoglycan layer of bacterial cell walls. Peptidoglycan is a strong structural molecule specific to the cells walls of bacteria. 5 Prepared by Dr.Ebtesam Salem  Chemistry of Cephalosporin The main difference between the two is that cephalosporins contain dihydrothiazine ring, while penicillin contains a thiazolidine ring. Nucleous of the most cephalosporin is 7- amino- cephalosporanic acid (7-ACA). 6  Nomenclatures Cephalosporins are named in the following ways: 1. Chemical abstracts: 2. Cephem derivatives: Cephem is the name given to the unsubstituted bicyclic lactam. 7 Prepared by Dr.Ebtesam Salem  Cephalosporins advantages over penicillins Increased acid stability compare to penicillins. Most of the drugs have better absorption than penicillins. Cephalosporins are also more difficult for β- lactamases to hydrolyze Broad antimicrobial spectrum. Increased activity against resistant microorganisms. Decreased allergenicity. Increased tolerence than penicillins 8 Prepared by Dr.Ebtesam Salem  Semisynthetic Derivatives Modification of side chains has been used to create a whole new class of cephalosporin antibiotics. Modification of side-chains at position 7 of the lactam ring seems to affect the antibacterial activity while position 3 of the dihydrothiazine ring alters pharmacokinetic properties 9  In the preparation of semisynthetic cephalosporins, the following improvements are sought: Increased acid stability, Improved pharmacokinetic properties, particularly Better oral absorption,  Broadened antimicrobial spectrum, Increased activity against resistant microorganisms Decreased allergenicity 10 Prepared by Dr.Ebtesam Salem  Oral Cephalosporins The oral activity of cephalosprins is attributed to  increased acid stability of the lactam ring, resulting from the presence of a protonated amino group on the 7-acylamino portion.  The absence of the leaving group at the 3- position.  The esterification of the 3-carboxylic acid group to form acid-stable, lipophilic esters that undergo hydrolysis in the plasma. 11 Prepared by Dr.Ebtesam Salem  β-Lactamase Resistance The susceptibility of cephalosporins to various lactamases is varied. The introduction of polar substituents in the aminoacyl moiety of cephalosporins appears to confer stability to some β-lactamases Two structural features confer broadly based resistance to β-lactamases include: (a) an alkoximino function in the aminoacyl group and (b) a methoxyl substituent at the 7-position of the cephem nucleus having α stereochemistry. 12 Steric factors also may be important 13 Prepared by Dr.Ebtesam Salem  SAR of cephalosporins 14 Prepared by Dr.Ebtesam Salem  SAR of cephalosporins  7-Acylamino substituents: 15 Prepared by Dr.Ebtesam Salem 16 Prepared by Dr.Ebtesam Salem  C-3 substituents: Acetyloxy group is readily is hydrolyzed by esterase to form less active product. The nature of C-3 substituents influences pharmacokinetic properties as well as antibacterial activity. 17 Prepared by Dr.Ebtesam Salem  Replacement of acetoxy group at C-3 position with —CH3, Cl has resulted in orally active compounds. 18 Prepared by Dr.Ebtesam Salem Other modifications a. Replacement of sulphur with oxygen leads to oxacepam with increased antibacterial activity, Similarly, replacement of sulphur with methylene group has greater chemical stability and a longer half-life. b. The carboxyl group has been converted into ester prodrugs to increase bioavailability of cephalosporins, and these can be given orally as well. c. The antibacterial activity depends on the olefinic linkage and their activity is lost due to the ionization of double bond. 19 Prepared by Dr.Ebtesam Salem 20  Classification of cephalosporins Cephalosporins are divided into first-, second-, third-, and fourth-generation agents, based roughly on their time of discovery and their antimicrobial properties. In general, progression from first to fourth generation is associated with a  Broadening of the Gram-negative antibacterial spectrum  Reduction in activity against Gram-positive organisms, and  Enhanced resistance to β lactamases 21 Prepared by Dr.Ebtesam Salem 1ST Generation Cephalosporins These drugs are very active against Gram-positive cocci (such as Pneumococci, Streptococci, and Staphylococci). They do not cross BBB. It designed as an orally active, semisynthetic cephalosporin. The α-amino group of cephalexin renders it acid stable, Cephalexin 22 Prepared by Dr.Ebtesam Salem  7-acyl group is the hydroxylphenylglycyl. Has prolonged duration of action related to relatively slow urinary excretion of the drug compared with Cefadroxil other cephalosporins It is the only cephalosporin derivative available in both oral and parenteral dosage forms. It closely resembles cephalexin chemically (it may be regarded as a partially hydrogenated derivative of Cephradine cephalexin) and has very similar antibacterial and pharmacokinetic properties. 23 Prepared by Dr.Ebtesam Salem 2nd Generation Cephalosporins They have a greater gram-negative spectrum while retaining some activity against gram- positive bacteria. They are also more resistant to β-lactamase. It differs structurally from cephalexin in that the 3- methyl group has been replaced by a chlorine atom. It is moderately stable in acid Cefaclor 24 Prepared by Dr.Ebtesam Salem  It is the first of a series of - methoximinoacyl–substituted cephalosporins alkoximino substituent is associated with -lactamase stability oral prodrug derivative of cefuroxime can by produed which is hydrolyzed to cefuroxime by intestinal and/or plasma Cefuroxime enzymes 25 3rd Generation Cephalosporins Third-generation drugs exhibit the fallowing: (a) Extended antibacterial spectrum, include Pseud. aeruginosa; (b) Less activity on gram-positive bacteria than first and second generation; (c) Most active on gram-negative bacteria; (d) High stability with β-lactamase; (e) Easy penetrate to different tissues, and then have broad distribution; (f) Little kidney toxicity 26 Prepared by Dr.Ebtesam Salem  Cefotaxime was the first third- generation cephalosporin to be introduced. It possesses excellent broad-spectrum activity against Gram-positive and Gram negative aerobic and anaerobic bacteria. Cefotaxime It is a βlactamase–resistant cephalosporin. It has high protein binding in the plasma and slow urinary excretion which contribute to the prolonged duration of action It has highly acidic heterocyclic system on the 3-thiomethyl group which believed to confer the unique 27 pharmacokinetic properties of this agent  Cefixime is the first orally active, third-generation cephalosporin is a broad-spectrum cephalosporin that is resistant to many β- lactamases. The comparatively long half-life of cefixime allows it to be administered on a twice-a-day schedule 28 Prepared by Dr.Ebtesam Salem 4th Generation Cephalosporins Good affinity for the transpeptidase enzyme. Low affinity for some β-lactamases. Cross BBB and effective in meningitis cefpirome is the first fourth generation cephalosporin. It is a newer parenteral, β- lactamase–resistant cephalosporin with a quaternary ammonium group at the 3-position of the cephem nucleus 29 Prepared by Dr.Ebtesam Salem  Cefepime is a parenteral, β- lactamase–resistant cephalosporin that is chemically and microbiologically similar to cefpirome. It also has a broad antibacterial spectrum, with significant activity against both Gram-positive and Gram- Cefepime negative bacteria 30 5th Generation Cephalosporins Active against Methicillin-resistant: Staphylococcus aureus  Penicillin-resistant: Streptococcus pneumonia 31 Prepared by Dr.Ebtesam Salem 32  Other β-Lactam antibiotics Carbapenem They are a class of β-lactam antibiotics with a broad spectrum of antibacterial activity. They have a structure that renders them highly resistant to most β-lactamases. Carbapenem Examples:  Imipenem, Meropenem, Ertapenem 33 Prepared by Dr.Ebtesam Salem Monobactam Monobactams are drugs with a monocyclic β- lactam ring. They are relatively resistant to beta-lactamases and active aganist Gram-negative rods They have no activity against Gram-positive bacteria or anaerobes. Examples: Aztreonam, Tigemonam. 34 Prepared by Dr.Ebtesam Salem  References 1. Wilson and Gisvolds textbook of organic medicinal and pharmaceutical chemistry by John H. Black and John M. Beale, jr. 12th edition, Lippincott Williams and Wilkings 2011. 2. Foyes principle of medicinal chemistry by David H. Williams, Thomas L. Leuke, Williams O. Foye. Lippincott William and Wilkins. 7th edition, 2013 35 Prepared by Dr.Ebtesam Salem