Abstract
We present the synthesis and biological evaluation of the prototype of a new class of cephalosporins, containing an additional isolated beta lactam ring with two phenyl substituents. This new compound is effective against Gram positive microorganisms, with a potency similar to that of ceftriaxone, a cephalosporin widely used in clinics and taken as a reference, and with no cytotoxicity against two different human cell lines, even at a concentration much higher than the minimal inhibitory concentration tested. Additionally, a deep computational analysis has been conducted with the aim of understanding the contribution of its moieties to the binding energy towards several penicillin-binding proteins from both Gram positive and Gram negative bacteria. All these results will help us developing derivatives of this compound with improved chemical and biological properties, such as a broader spectrum of action and/or an increased affinity towards their molecular targets.
Highlights
Beta lactam antibiotics are considered among the most important drugs for the history of mankind, and, due to their ease of delivery, potent activity, relatively low toxicity and low costs, they still remain among the most frequently used classes of antimicrobial drugs [1]. Their targets are the penicillin-binding proteins (PBPs), a large family of enzymes not present in eukaryotes, which are involved in the synthesis and maintenance of the peptidoglycan, the main component of the bacterial cell wall
Study of a new cephalosporin analogue additional beta lactam ring with different substituents, joined to the amino-nitrogen of 6-aminopenicillanic acid (6-APA) scaffold via an amide bond.We have shown that the compounds obtained in that way exhibited antibacterial activity against Gram positive bacteria (microbial inhibitory concentration (MIC) in the micromolar range), with no or minimal in vitro cytotoxicity at a concentration comparable or higher than the MICs found in examined Gram positive bacteria [17]
We have extended this approach to the 7-aminocephalosporanic (7-ACA) acid, and we have synthesized the prototype of a new class of cephalosporin analogues, testing it for its efficacy towards both Gram positive and negative bacteria, and its safety towards eukaryotic cell lines
Summary
Beta lactam antibiotics are considered among the most important drugs for the history of mankind, and, due to their ease of delivery, potent activity, relatively low toxicity and low costs, they still remain among the most frequently used classes of antimicrobial drugs [1]. Their targets are the penicillin-binding proteins (PBPs), a large family of enzymes not present in eukaryotes, which are involved in the synthesis and maintenance of the peptidoglycan, the main component of the bacterial cell wall.
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