Lecture 4 Cephalosporines -Non-classical PDF

New Mansoura University Faculty of Pharmacy Pharm D Program ___________________________________________________________________________ Department of Pharmaceutical Medicinal Chemistry Program: : Pharm D Progr...

New Mansoura University Faculty of Pharmacy Pharm D Program ___________________________________________________________________________ Department of Pharmaceutical Medicinal Chemistry Program: : Pharm D Program Course Title : Medicinal Chemistry-I Course Code: PMC-306  Chemotherapy (Antibacterial agents)  The second major group of β-lactam antibiotics.  The first cephalosporin (cephalosporin C) was derived from a fungus obtained in the mid 1940s.  In cephalosporin the bicyclic system containing four-membered β-lactam ring fused to a six-membered dihydrothiazine ring*.  The cephalosporins act in a manner similar to that of the penicillins  Remember! Penicillin   There is a limited number of places where modifications can be made, but there are more possibilities than with penicillins.  To date, the more useful semisynthetic modifications of the basic 7-ACA nucleus have resulted from:-  Acylation of the 7-amino group with different acids (Variations of the 7-acylamino side chain).  Nucleophilic substitution or reduction of the acetoxy group.  Extra substitution at carbon 7.  The first generation cephalosporins  They are primarily active against Gram (+) bacteria.  They are not significantly active against Gram(-) bacteria (only some Gram-negative bacilli.  Lack activity against Pseudomonas aeruginosa.  They are not effective against methicillin-resistant Staph. aureus.  The second generation cephalosporins  They generally retain the anti Gram (+) activity and add better antiGram (-) activity.  The third generation cephalosporins  They are less active against staphylococci than the first generation agents but are much more active against Gram (-) bacteria than either the first or the second generation drugs.  The fourth generation cephalosporins  They have an antibacterial spectrum like the third-generation drugs but add Pseudomonas aeruginosa and some enterobacteria that are resistant to the third- generation cephalosporins.  They are also more active against some Gram (+) organisms.  Cephalothin (Cefalotin) has relatively short duration of action due to rapid hydrolysis of acetyloxy group at C-3 by esterase enzyme to less active alcohol which undergoes lactonization to inactive lactone.  The acetyloxy group is important to the mechanism of inhibition and acts as a good leaving group.  Replacing the acetoxy group (ester) with a metabolically stable pyridinium group gives cephaloridine.  The pyridine can still act as a good leaving group for the inhibition mechanism, but is not cleaved by esterases.  Cephaloridine exists as a zwitterion and is poorly absorbed through the gut wall and has to be injected.  -Radine -ALEX -Droxil  They have a 3-CH3 group which help oral absorption but it is bad for activity as it is not a good leaving group.  The electron-withdrawing character of the protonated –NH2 group improves the stability of the β-lactam of the cephalosporin, leading to orally active drugs.  Properties:  Excellent oral activity, why?  Broad spectrum activity (G +ve) & some Gram-negative bacilli.  Poor -lactamase stability.  Poor ability to penetrate cerebrospinal fluids.  Lack activity against Pseudomonas aeruginosa.  Cephradine is the dihydro-analog of cephalexin and undergoes aromatization in the body producing cephalexin. Oral Parenteral  The 3-substitution pattern in addition to the electron-withdrawing character of the protonated –NH2 improves the stability of the β-lactam ring → orally active drugs.  Cefaclor is less active against Gram-negative bacteria than the other second- generation cephalosporins.  Parenteral and -lactamase Stable agents  Cefuroxime  It has A syn (Z) methoxyimino substituent is associated with β-lactamases stability result from its steric effect.  Z-oxime was as much as 20,000-fold more stable than the E-oxime  Very safe and has a wide spectrum of activity.  It is useful against organisms resistant to penicillin.  Poor activity against Pseudomomnas aeruginosa due to lack of penetration of the drug. Oral Parenteral  Replacing the furan ring of the Cefuroxime with an aminothiazole ring:-  Enhances the penetration through the outer membrane of Gram-negative bacteria  Increase affinity for the transpeptidase enzyme (PBPs).  As a result, third (and fourth) generation cephalosporins containing this ring have a marked increase in activity against Gram-negative bacteria*.  A variety of such structures have been prepared with different substituents at position 3 to vary the pharmacokinetic properties.  Cefotaxime has a metabolically vulnerable acetoxy group attached to C-3 and loses about 90% of its activity when this is hydrolyzed.  It has greater anti–Pseudomonas aeruginosa activity.  It has metabolically stable, activating and highly acidic 3-thio-2-methyl-1,2-dihydro- 1,2,4-triazine-5,6-dione at C-3 that at normal pH, it forms an enolic sodium salt, and thus the commercial product is a disodium salt.  It is 95% serum bound and exhibits an extended serum profile making it suitable for once daily administration.  Greater anti–Pseudomonas aeruginosa activity.  It is the first-line drug for meningitis as it has the best CSF penetration and covers the bacteria causing meningitis. Parenteral  It contains Z-methoxyimine moiety at C-7 in addition to quaternary ammonium group at C-3*.  These features lead to:  Enhancing water solubility and ability to penetrate the outer membrane of Gram negative bacteria (have broader anti–Gram-negative activity than the third- generation).  Active vs. Gram +ve cocci (increasing antistaphylococcal activity).  Good affinity for the transpeptidase enzyme.  Greater β-lactamase stability (i.e. low affinity for β-lactamase).  They have excellant anti–Pseudomonas aeruginosa activity.  They contain “Ceft” + “ol” in their name  They contain 5-amino-1,2,4-thiadiazole moiety in the acyl side chain  Ceftaroline fosamil  It has activity against various strains of methicillin-resistant Staphylococcus aureus (MRSA) and multi-resistant Streptococcus pneumonia (MDRSP).  It acts as a prodrug for ceftaroline  The 1,3-thiazole ring at 3 position is thought to be important for its activity against MRSA. Fourth generation Fifth generation Choose the correct answer: Which of the following cephalosporins belongs to the second generation? a. Cefaclor b.Cefalexin c. Cefadroxil d. Cefradine Choose the correct answer: Which of the following cephalosporins is an oximinocephalosporin derivative? a. Cefuroxime b.Cefotaxime c. Ceftriaxone d. All of the followings II– Non-classical β-lactams 1- Carbapenems  It is potent, with an extraordinarily broad range of activity against Gram-positive and Gram negative bacteria, including P. aeruginosa.  It shows a high resistance to β-lactamases.  It combines in one molecule the functional features of the best of the β-lactam antibiotics as well as the β-lactamase inhibitors*.  It shows poor metabolic and chemical stability, and is not absorbed from gut.  It is subjected to hydrolytic inactivation by renal dehydropeptidase-I (DHP-I) →unacceptably short t1/2 in vivo and higher incidence of nephrotoxicity.  penem  Imipenem is N-formimidoyl derivative of thienamycin.  Administration is by IM injection or by IV infusion.  Imipenem is metabolized by renal dehydropeptidase-l (DHP-1) which deactivates imipenem through hydrolysis of the β-lactam producing kidney toxic metabolites.  Cilastatin (dehydropeptidase-1 inhibitor) is co-administered with imipenem to protect it from metabolism*.  penem  Substituents at the 3-position affect the spectrum of antibacterial activity by influencing penetration into bacteria  It is more active against Gram-negative and anaerobic bacteria than imipenem (but less active against Gram-positive species).  It has an extra methyl group at C-4 which conveys intrinsic resistance and hence stability to hydrolysis by renal DHP-1 so has lower incidence of nephrotoxicity and can be administered alone.  It is administered by IV injection or infusion.  Approved by the FDA on 2017 to be used in combination with vaborbactam for treating complicated urinary tract infection (cUTI).  penem  Doripenem is the newest of the approved carbapenems.  It also contains the 4-β-methyl group, which confers stability toward renal DHP-1, so it is given as a single agent.  It is similar in spectrum to imipenem and meropenem but is considered more potent against Pseudomonas species. II– Non classical β-lactams 2- Monobactam  nam  The sulfamic acid moiety attached to the β-lactam ring resemble COOH in penicillins.  The strongly electron-withdrawing character of the sulfamic acid group probably also makes the β-lactam bond more subjected to hydrolysis.  The α-oriented methyl group at C-2 is associated with the stability of aztreonam toward β-lactamases. II– Non-classical β-lactams Choose the correct answer: All of the following drugs are carbapenems EXCEPT: a. Thienamycin b. Imipenem c. Aztreonam d. Meropenem 41 42