Organic Pharmaceutical Chemistry: Cephalosporin Generations Overview

Lec 6 4th stage Organic Pharmaceutical Chemistry III 2018-2019 Assist prof. Dr.Rita Sabah Elias College of Pharmacy, university of Basrah Textbook of Organic medicinal and pharmaceutical chemistry Wilson and Gisvold s

1st generation Cephalothin Sodium SAR :- Orally inactive due to the hydrolysis of C3-acetoxymethyl group under acidic condition and formation of inactive lacton. Use as IM and IV only. Polar thienyl ring provides activity against some G- organism. Resistance to -lactamase to certain extent

Cephapirin Sodium:- It closely resembles cephalothin in chemical and pharmacokinetic properties SAR :- Orally inactive due to the hydrolysis of C3-acetoxymethyl group under acidic condition and formation of inactive lacton. Use as IM and IV only. Polar mercapto group provides activity against some G- organism. Resistance to -lactamase to certain extent.

2nd generation Cefoxitin Sodium, Sterile SAR :- C3-Carbamoxymethyl group is acid liable used as IM, IV injection. Thienyl ring provides broad spectrum which is enhanced by unique C7-OCH3 group. Ring system is - lactamase resistance, may be due in part to 7- methoxy group.

Cefuroxime Sodium 1- Cefuroxime is the first of a series of -methoximinoacyl substituted cephalosporins. 2- A syn alkoximino substituent is associated with -lactamase stability in these cephalosporins.

3rd generation This group of antibiotics are characterized by certain specific substituent at C- 3 such as (N-methylthiotetrazole) or with specific oxime ether group at C- . Cefoperazone Sodium, Sterile SAR:- C- substituted with amino diketopiperazine derivative like that seen in piperacillin. Sensitive to some - lactamase. Similar in spectrum of activity to moxam

Cefotaxime Sodium, Sterile SAR:- The syn isomer of cefotaxime is significantly more active than the anti-isomer against -lactamase producing bacteria. The C-3 substituent is acid liable.

Ceftizoxime Sodium, Sterile SAR:- C-3 with no substituent, thus C3-C4 exist as CH. Good -lactamase resistance, with broad spectrum of activity.

Ceftazidime Sodium, Sterile C- is substituted with 2-methylpropionicoxaminoacyl group that confers -lactamase resistance and, more selectivity to G- bacteria due to polarity of the group which increased permeability through the porin channels of the cell envelope a pyridinium group at the 3-position that confers zwitterionic properties on the molecule.

Ceftibuten SAR:- Analogue of oximino cephalosporins in which an olefinic methylene group (C=CHCH2-) with Z stereochemistry has replaced the syn oximino (C=NO-) group. This isosteric replacement result in a compound with resistance to -lactamases, enhanced chemical stability, and is orally active. Showed excellent potency against most members of enterobacteriaceae.

4th generation Cefpirome SAR:- C-3 carbon substituted with ammonium group (pyrimidinium head), provided greater activity toward G+ and G- bacteria than first, second and third generation. Its broad spectrum includes methicillin-sensitive staphylococci, penicillin-resistant pneumococci, and -lactamase producing strains of E. coli, The 2-amino thiazole and C- , oxime ether are similar to those found in 2nd generation cephalosporins.

Cefepime SAR:- C-3 carbon substituted with ammonium group (pyrimidinium head). C- substituted with oxime ether and 2-amino thiazole similar to that of cefpirome. It also has a broad antibacterial spectrum, with significant activity against both Gram-positive and Gram-negative bacteria, including streptococci, staphylococci, Pseudomonas spp., and the Enterobacteriaceae

General SAR for Cephalosporins C-3, acetoxymethyl liable to acidic conditions C-3 carbamate, relatively stable to acidic condition. C-3 = H, CH3, Cl, C=CH2-CH=CHCH2, -CH2-O-CH3 provide oral activity, or acid stability. C-7= -OCH3, provide greater resistance to -lactamase. C- = oxime ether broaden spectrum of activity and -lactamase resistance. C- = oxime ether with acidic founctional group ( carboxyl) increase spectrum of activity in a particular towards G- microorganism. C-3 thiomethyl heterocyclic group usually are of second generation cephalosporine. C-3 methylene immonium ion provide greater stability to -lactamase and broader spectrum of activity and most of these antibiotics are either third or fourth generation cephalosporins. C- aryl or aryl heterocyclic contribute to the spectrum of activity, in general aryl heterocyclic classified within 2nd, 3rd, and recently 4th generation cephalosporins.

MONOBACTAMS The development of useful monobactam antibiotics began with the independent isolation of sulfazecin and other monocyclic -lactam antibiotics from saprophytic soil bacteria in Japan and the United States. Sulfazecin was found to be weakly active as an antibacterial agent but highly resistant to -lactamases. Extensive SAR studies eventually led to the development of aztreonam, which has useful properties as an antibacterial agent. Early work established that the 3-methoxy group, which was in part responsible for -lactamase stability in the series, contributed to the low antibacterial potency and poor chemical stability of these antibiotics. A 4- methyl , however, increases stability to -lactamases and activity against Gram- negative bacteria at the same time .Unfortunately, potency against Gram-positive bacteria decreases.4,4-Gem-dimethyl substitution slightly decreases antibacterial potency after oral administration.

Products Aztreonam Disodium SAR:- Monocyclic lactam with electron withdrawing group at the nitrogen atom (sulfonic acid, SO3H) to facilliate ring opening of the lactam ring. The C- normally present in pencillins was converted to oxime derivative (isobutyric acid oximinoacyl group). Highly stable to -Lactamase( resistance to -Lactamase). Highly active against Gram-negative bacteria, inactive against Gram-positive bacteria and anaerobes. Poor oral activity.

Tigemonam SAR:- Investigational monobactam, with similar spectrum of activity of aztreonam. highly resistant to -lactamases