Synthesis and biological evaluation of the progenitor of a new class of cephalosporin analogues, with a particular focus on structure-based computational analysis

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.

Computational analysis of the interactions of a novel cephalosporin derivative with β-lactamases

“…As already shown for the interactions with PBPs [9], the two diastereoisomeric forms of the 7-ACA derivative show no significant differences in the interaction with these enzymes, confirming that their active sites are not selective towards this property. Similarly, the predicted binding score when the isolated 2-azetidinone ring is reactive towards the acylation is consistently higher than the score predicted when the β-lactam ring belonging to the 7-ACA moiety is the target for the acylation reaction.…”

“…Figure 2 shows the different diastereoisomers of the 7-ACA derivative in the binding pocket of wild type TEM-1 β-lactamase (PDB code: 1XPB). The predicted binding scores of the 7-ACA derivative for the different TEM-1 enzymes are similar to those predicted for several E. coli PBPs [9], and no significant differences are predicted between the wild type and mutant forms of TEM-1. The predicted binding scores of ceftriaxone, instead, tend to be lower in the case of TEM-1 with respect to PBPs [9].…”

“…The predicted binding scores of the 7-ACA derivative for the different TEM-1 enzymes are similar to those predicted for several E. coli PBPs [9], and no significant differences are predicted between the wild type and mutant forms of TEM-1. The predicted binding scores of ceftriaxone, instead, tend to be lower in the case of TEM-1 with respect to PBPs [9]. Although the difference is not fully significant in absolute values, this tendency is conserved across the various PBP with respect to all TEM-1.…”

“…Moreover, the 7-ACA derivative (Fig. 1) showed better antimicrobial activity against S. aureus , one of the main pathogens responsible for nosocomial infections [8, 9]. An extended computational analysis of this compound allowed to study the interactions between this molecule and some candidate target PBPs.…”

“…The results showed that this compound is potentially able to interact both with Gram-positive and Gram-negative enzymes, and that the 7-ACA nucleus is the preferred moiety targeting these enzymes, but also the isolated 2-azetidinone ring can interact with the active site of all PBPs. Moreover, a more favorable binding energy towards PBP2a, isolated from a multi-resistant S. aureus strain, was predicted for 7-ACA with respect to ceftriaxone [9]. All these data suggest that the 7-ACA derivative is a promising lead compound to develop a new class of antibiotics.

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