Design, Development and Synthesis of Novel Cephalosporin Group of Antibiotics

Abstract

Cephalosporins are ┚lactam antibiotics. In cephalosporin C, four membered ┚lactam ring (which is mainly responsible for the activity) is fused with six membered dihydrothiazine ring to form the basic nucleus, 7-aminocephalosporanic acid (7-ACA) and to which ┙aminoadipic acid side chain is attached through an amide bond (Fig 1). (Mandell and Sande,1991)Although cephalosporin was found to be active against large number of pathogenic bacteria (Medeiros, 1997) but the main hindrance in its application is its low stability. Also, occurrence of bacterial strains that are resistant to already existing antibiotics such as methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant E. faecalis (VRE) has led to the search of new semisynthetic cephalosporins with better solubility and new mechanism of action. Only cephalosporin C is found naturally, so it’s chemical modification allowed production of a whole series of semisynthetic cephalosporins which can be used as therapeutics to fight organisms that have become penicillin resistant. Chemical modifications of cephalosporin C resulted in new cephalosporin derivatives. These semisynthetic cephalosporins are classified based on their activity profile, the antibacterial spectrum. Each newer generation of cephalosporin has significantly greater Gram –ve antimicrobial properties than the preceding generations, (Stan,2004; Jones,1994; Jacoby,2000; Babini and Livermore, 2000) in most cases with decreased activity against Gram +ve organism. Fourth generation cephalosporins are known to have true broad spectrum activity. (Wilson,1998; Tzouvelekis et al., 1998) In the past decade, even though the cephalosporin antibiotics have made remarkable progress and contribution in the treatment of acute diseases originated from pathogenic infection in clinics, many efforts still exist to achieve the well balanced broad spectrum and to improve beta-lactamase stability. 7┙formamido cephalosporins were isolated as fermentation product of various gram negative bacteria. The development of a new antibiotic focuses mainly with the study and characterization of its mechanism of its activity (Table 1). The ┚-lactam antibiotics like penicillin, cephalosporins, vancomycin, etc. are specific inhibitor working against bacterial cell wall (peptidoglycan) synthesis but newer strains have ┚-lactamase activity which destroys most of the ┚-lactam antibiotics and thus make them resistant to it. However, cephalosporins proved to be more stable to ┚-lactamase. Cephalosporin-C (CPC) shows similarity to in structure with the penicillin in having an acyl side chain attached to an